Novel heterocyclic compounds and salts thereof and medicinal use of the same

ABSTRACT

A heterocyclic compound of the formula [I] 
                 
 
     wherein R 1  is hydrogen atom or lower alkyl, R 2  is hydrogen atom, alkyl optionally having a substituent and the like, R 3  is hydrogen atom, lower alkyl and the like, A is a single bond or &gt;N—R 5  wherein R 5  is hydrogen atom or lower alkyl, B is lower alkylene, and Y is aryl optionally having a substituent and the like, and a pharmaceutically acceptable salt thereof show a hypoglycemic action, a blood hypolipidemic action, an insulin resistance-improving action and a PPAR activating action, and are useful as a hypoglycemic agent, a hypolipidemic agent, an insulin resistance improver, a therapeutic agent of diabetes, a therapeutic agent of diabetic complication, a glucose tolerance improver, an anti-atherosclerosis agent, an anti-obesity agent, an antiinflammatory agent, an agent for the prophylaxis or treatment of PPAR-mediated disease and an agent for the prophylaxis or treatment of syndrome X.

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to a novel heterocyclic compoundand a pharmaceutically acceptable salt thereof, which have ahypoglycemic action, a blood hypolipidemic action, an insulinresistance-improving action or a PPAR (peroxisome proliferator-activatedreceptor)-activating action. The present invention also relates to apharmaceutical composition comprising the above-mentioned novelheterocyclic compound or a pharmaceutically acceptable salt thereof.Furthermore, the present invention relates to a hypoglycemic agent, ahypolipidemic agent, an insulin resistance improver, a therapeutic agentof diabetes, an anti-diabetic complication agent (i.e., a therapeuticagent of diabetic complication), a glucose tolerance improver, ananti-atherosclerosis agent, an anti-obesity agent, an antiinflammatoryagent, an agent for the prophylaxis or treatment of PPAR-mediateddisease and an agent for the prophylaxis or treatment of syndrome X, allof which comprising the above-mentioned novel heterocyclic compound or apharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

[0002] As a therapeutic agent of diabetes, biguanide compounds having,as a main action, an inhibitory action on glucose absorption via theintestinal tract and on glucose release from the liver, sulfonylureacompounds having an accelerating action on insulin secretion as a mainaction, insulin and the like have been employed. However, biguanidecompounds cause lactic acidosis, and sulfonylurea compounds sometimescause serious hypoglycemia due to their strong hypoglycemic action.Therefore, a due care should be given when in use of these compounds. Inrecent years, there have been active researches and developments of atherapeutic agent of diabetes, which is free of these defects, with theconsequence that various compounds having an insulinresistance-improving action have been found.

[0003] The insulin resistance is important as a cause of non-insulindependent diabetes mellitus (NIDDM), along with decrease in the insulinsecretion. Therefore, the development of a pharmaceutical agent thatimproves insulin resistance has been desired. Various thiazolidinecompounds are known as the agent capable of improving the insulinresistance. As these compounds, for example,5-[4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]benzyl]-2,4-thiazolidinedione(general name: troglitazone) is described in JP-B-2-31079,5-[[4-[2-(5-ethyl-pyridin-2-yl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione(general name: pioglitazone) is described in JP-B-5-66956, and5-[[4-[2-[N-methyl-N-(pyridin-2-yl)amino]ethoxy]phenyl]methyl]-2,4-thiazolidinedione(general name: rosiglitazone) is described in JP-A-1-131169.

[0004] It is therefore an object of the present invention to provide acompound having a hypoglycemic action, a blood hypolipidemic action, aninsulin resistance-improving action and a PPAR activating action, whichhas a structure completely different from that of conventionalcompounds, thereby to increase the diversity in and to broaden the rangeof selection from hypoglycemic agents, hypolipidemic agents, insulinresistance improvers, therapeutic agents of diabetes, therapeutic agentsof diabetic complications, glucose tolerance improvers,anti-atherosclerosis agents, anti-obesity agents, antiinflammatoryagents, agents for the prophylaxis or treatment of PPAR-mediated diseaseand agents for the prophylaxis or treatment of syndrome X.

DISCLOSURE OF THE INVENTION

[0005] The present inventors have conducted intensive studies in anattempt to solve the above-mentione problems and found that aheterocyclic compound having a novel structure of the formula [I]

[0006] wherein

[0007] R¹ is hydrogen atom or lower alkyl,

[0008] R² is hydrogen atom, alkyl optionally having a substituent,cycloalkyl, cycloalkylalkyl, aryl optionally having a substituent,arylalkyl optionally having a substituent, alkenyl optionally having asubstituent, alkynyl optionally having a substituent, heterocyclic alkyloptionally having a substituent or —COR⁴

[0009] wherein R⁴ is hydrogen atom, alkyl optionally having asubstituent, aryl optionally having a substituent, alkenyl optionallyhaving a substituent, arylalkyl optionally having a substituent orheterocyclic residue optionally having a substituent,

[0010] R³ is hydrogen atom, lower alkyl or lower alkoxy,

[0011] A is a single bond or >N—R⁵ wherein R⁵ is hydrogen atom or loweralkyl,

[0012] B is lower alkylene, and

[0013] Y is aryl optionally having a substituent or an aromaticheterocyclic residue optionally having a substituent

[0014] and a pharmaceutically acceptable salt thereof have ahypoglycemic action, a blood hypolipidemic action, an insulinresistance-improving action and a PPAR activating action, which resultedin the completion of the invention.

[0015] Accordingly, the present invention relates to the following.

[0016] [1] A heterocyclic compound of the formula [I]

[0017] wherein

[0018] R¹ is hydrogen atom or lower alkyl,

[0019] R² is hydrogen atom, alkyl optionally having a substituent,cycloalkyl, cycloalkylalkyl, aryl optionally having a substituent,arylalkyl optionally having a substituent, alkenyl optionally having asubstituent, alkynyl optionally having a substituent, heterocyclic alkyloptionally having a substituent or —COR⁴

[0020] wherein R⁴ is hydrogen atom, alkyl optionally having asubstituent, aryl optionally having a substituent, alkenyl optionallyhaving a substituent, arylalkyl optionally having a substituent orheterocyclic residue optionally having a substituent

[0021] R³ is hydrogen atom, lower alkyl or lower alkoxy,

[0022] A is a single bond or >N—R⁵ wherein R⁵ is hydrogen atom or loweralkyl,

[0023] B is lower alkylene, and

[0024] Y is aryl optionally having a substituent or an aromaticheterocyclic residue optionally having a substituent (hereinafter to bereferred to as

[0025] heterocyclic compound [I]), and a pharmaceutically acceptablesalt thereof;

[0026] [2] the heterocyclic compound of the above-mentioned [1] wherein,in the formula [I],

[0027] R¹ is hydrogen atom or lower alkyl,

[0028] R² is hydrogen atom, alkyl optionally having a substituent,cycloalkyl, cycloalkylalkyl, aryl optionally having a substituent,arylalkyl optionally having a substituent or —COR⁴ wherein R⁴ ishydrogen atom, alkyl optionally having a substituent, aryl optionallyhaving a substituent or arylalkyl optionally having a substituent,

[0029] R³ is hydrogen atom, lower alkyl or lower alkoxy,

[0030] A is a single bond or >N—R⁵ wherein R⁵ is hydrogen atom or loweralkyl,

[0031] B is lower alkylene, and

[0032] Y is aryl optionally having a substituent or an aromaticheterocyclic residue optionally having a substituent, and apharmaceutically acceptable salt thereof;

[0033] [3] the heterocyclic compound of the above-mentioned [1] wherein,in the formula [I],

[0034] R¹ is hydrogen atom or lower alkyl,

[0035] R² is hydrogen atom, alkyl, cycloalkylalkyl, arylalkyl optionallyhaving a substituent, alkenyl, alkynyl, heterocyclic alkyl or —COR⁴wherein R⁴ is alkyl, alkenyl or aryl,

[0036] R³ is hydrogen atom or lower alkoxy,

[0037] A is a single bond or >N—R⁵ wherein R⁵ is lower alkyl,

[0038] B is lower alkylene, and

[0039] Y is aryl or an aromatic heterocyclic residue optionally having asubstituent,

[0040] and a pharmaceutically acceptable salt thereof;

[0041] [4] the heterocyclic compound of the above-mentioned [1] wherein,in the formula [I],

[0042] R¹ is hydrogen atom or lower alkyl,

[0043] R² is hydrogen atom, alkyl, cycloalkylalkyl, arylalkyl optionallyhaving a substituent or —COR⁴ wherein R⁴ is alkyl or aryl,

[0044] R³ is hydrogen atom,

[0045] A is a single bond or >N—R⁵ wherein R⁵ is lower alkyl,

[0046] B is lower alkylene, and

[0047] Y is an aromatic heterocyclic residue optionally having asubstituent,

[0048] and a pharmaceutically acceptable salt thereof;

[0049] [5] the heterocyclic compound of the above-mentioned [1] wherein,in the formula [I],

[0050] Y—A— is

[0051] wherein R^(A) is isopropyl or tert-butyl,

[0052] R^(B) is isopropyl or tert-butyl,

[0053] R^(C) is isopropyl, tert-butyl, phenyl, thiophen-2-yl,2-methylpropenyl, 3-butenyl, cyclopropyl, 1-butenyl or2,2-dimethylpropyl, and a pharmaceutically acceptable salt thereof;

[0054] [6] the heterocyclic compound of the above-mentioned [1] wherein,in the formula [I],

[0055] Y—A— is

[0056] wherein R^(A) is isopropyl or tert-butyl,

[0057] R^(B) is isopropyl or tert-butyl,

[0058] R^(C) is isopropyl, tert-butyl, phenyl, thiophen-2-yl,2-methylpropenyl or 3-butenyl,

[0059] and a pharmaceutically acceptable salt thereof;

[0060] [7] the heterocyclic compound of the above-mentioned [1] wherein,in the formula [I],

[0061] Y—A— is

[0062] and a pharmaceutically acceptable salt thereof;

[0063] [8] the heterocyclic compound of the above-mentioned [1] wherein,in the formula [I],

[0064] Y—A— is

[0065] and a pharmaceutically acceptable salt thereof;

[0066] [9] the heterocyclic compound of the above-mentioned [1] whereinthe heterocyclic compound of the formula [I] is any of the followingcompounds (1) to (67):

[0067] (1)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0068] (2)2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0069] (3)2-acetyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0070] (4)2-methyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0071] (5)2-hexanoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0072] (6)2-hexyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0073] (7)2-isobutyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0074] (8)2-cyclohexylmethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0075] (9)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(3-phenylpropyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0076] (10) 2-benzoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,

[0077] (11)2-benzyl-7-[2-(N-methyl-N-(pyridin-2-yl)amino)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0078] (12)2-benzyl-7-[2-(5-ethyl-pyridin-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0079] (13)2-benzyl-7-[2-(indolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0080] (14) ethyl2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,

[0081] (15) methyl7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,

[0082] (16)2-(4-methoxybenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0083] (17) ethyl2-(4-methoxybenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,

[0084] (18)2-(4-methylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0085] (19) ethyl2-(4-methylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,

[0086] (20)2-benzyl-7-[2-(6-carboxyindolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0087] (21)2-(4-fluorobenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0088] (22)2-(2,2-dimethylpropionyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0089] (23)2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0090] (24)2-benzyl-7-[2-(5-methyl-2-tert-butyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0091] (25)2-benzyl-7-[2-(5-methyl-2-(thiophen-2-yl)oxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0092] (26)2-benzyl-7-[2-(5-methyl-2-isopropyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0093] (27)2-butyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0094] (28)2-benzyl-7-{2-[5-methyl-2-(2-methylpropenyl)oxazol-4-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0095] (29)2-benzyl-7-{2-[2-(3-butenyl)-5-methyloxazol-4-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0096] (30)2-allyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0097] (31)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(2-propynyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0098] (32)2-(2-butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0099] (33)2-benzyl-7-[(indolin-3-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0100] (34)2-(3-butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0101] (35)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-pentanoyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0102] (36)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(4-pentenoyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0103] (37)2-(3-methyl-2-butenoyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0104] (38)2-(3,3-dimethylbutyryl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0105] (39)2-benzyl-7-methoxy-6-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3RS)-carboxylicacid,

[0106] (40)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0107] (41)2-benzyl-7-(3-methyl-3-phenylbutoxy)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0108] (42)2-benzyl-7-(3,3-dimethyl-4-phenylbutoxy)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0109] (43)2-benzyl-7-(2-isopropylbenzoxazol-6-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0110] (44)2-benzyl-7-(2-tert-butylbenzoxazol-6-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0111] (45)2-benzyl-7-(2-tert-butylbenzoxazol-5-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0112] (46)7-(2-tert-butylbenzoxazol-6-yl)methoxy-2-(2,2-dimethylpropyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0113] (47)2-benzyl-7-(2-isopropylbenzoxazol-5-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0114] (48)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0115] (49)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-[(pyridin-2-yl)carbonyl]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0116] (50) methyl2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,

[0117] (51)2-benzyl-7-[2-(2-cyclopropyl-5-methyloxazol-4-yl)-ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0118] (52)2-(3-methyl-2-butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0119] (53)2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-tert-butyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0120] (54)2-benzyl-7-[2-(1-butenyl)-5-methyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0121] (55)2-benzyl-7-[2-(2,2-dimethylpropyl)-5-methyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0122] (56) ethyl2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,

[0123] (57)7-(benzofran-2-ylmethoxy)-2-benzyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0124] (58)2-isobutyryl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0125] (59)7-[2-(benzofran-2-yl)ethoxy]-2-benzyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0126] (60)7-[2-(5-ethylpyridin-2-yl)ethoxy]-2-hexanoyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0127] (61)2-carboxymethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0128] (62)2-[3-(methoxycarbonyl)propionyl]-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0129] (63)2-[3-(ethoxycarbonyl)propyl]-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0130] (64)2-benzyl-6-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3RS)-carboxylicacid,

[0131] (65)2-(3-acetylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0132] (66)2-(2-acetylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, and

[0133] (67)2-benzyl-7-[(5-methyl-2-phenyloxazol-4-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, and a pharmaceutically acceptable salt thereof;

[0134] [10] the heterocyclic compound of the above-mentioned [9] whereinthe heterocyclic compound of the formula [I] is any of theabove-mentioned compounds (1) to (47), and a pharmaceutically acceptablesalt thereof;

[0135] [11] the heterocyclic compound of the above-mentioned [9] whereinthe heterocyclic compound of the formula [I] is any of theabove-mentioned compounds (1) to (21), and a pharmaceutically acceptablesalt thereof;

[0136] [12] a pharmaceutical composition comprising the heterocycliccompound of any of the above-mentioned [1] to [11] or a pharmaceuticallyacceptable salt thereof;

[0137] [13] a pharmaceutical agent comprising the heterocyclic compoundof any of the above-mentioned [1] to [11] or a pharmaceuticallyacceptable salt thereof, which is selected from the group consisting ofa hypoglycemic agent, a hypolipidemic agent, an insulin resistanceimprover, a therapeutic agent of diabetes, a therapeutic agent ofdiabetic complication, a glucose tolerance improver, ananti-atherosclerosis agent, an anti-obesity agent, an antiinflammatoryagent, an agent for the prophylaxis or treatment of PPAR-mediateddisease and an agent for the prophylaxis or treatment of syndrome X;

[0138] [14] a hypoglycemic agent comprising the heterocyclic compound ofany of the above-mentioned [1] to [11] or a pharmaceutically acceptablesalt thereof;

[0139] [15] a hypolipidemic agent comprising the heterocyclic compoundof any of the above-mentioned [1] to [11] or a pharmaceuticallyacceptable salt thereof;

[0140] [16] an insulin resistance improver comprising the heterocycliccompound of any of the above-mentioned [1] to [11] or a pharmaceuticallyacceptable salt thereof;

[0141] [17] a therapeutic agent of diabetic complications, comprisingthe heterocyclic compound of any of the above-mentioned [1] to [11] or apharmaceutically acceptable salt thereof; and

[0142] [18] a therapeutic agent of diabetes, comprising the heterocycliccompound of any of the above-mentioned [1] to [11] or a pharmaceuticallyacceptable salt thereof.

[0143] The novel heterocyclic compound of the formula [I]

[0144] wherein

[0145] R¹ is hydrogen atom or lower alkyl,

[0146] R² is hydrogen atom, alkyl optionally having a substituent,cycloalkyl, cycloalkylalkyl, aryl optionally having a substituent,arylalkyl optionally having a substituent, alkenyl optionally having asubstituent, alkynyl optionally having a substituent, heterocyclic alkyloptionally having a substituent or —COR⁴

[0147] wherein R⁴ is hydrogen atom, alkyl optionally having asubstituent, aryl optionally having a substituent, alkenyl optionallyhaving a substituent, arylalkyl optionally having a substituent orheterocyclic residue optionally having a substituent,

[0148] R³ is hydrogen atom, lower alkyl or lower alkoxy,

[0149] A is a single bond or >N—R⁵ wherein R⁵ is hydrogen atom or loweralkyl,

[0150] B is lower alkylene, and

[0151] Y is aryl optionally having a substituent or an aromaticheterocyclic residue optionally having a substituent

[0152] and a pharmaceutically acceptable salt thereof have ahypoglycemic action, a blood hypolipidemic action, an insulinresistance-improving action and a PPAR-activating action.

[0153] The alkoxycarbonyl in the present invention preferably has 2 to 5carbon atoms. Examples thereof include methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl and the like.

[0154] The lower alkyl at R¹, R³ and R⁵ is preferably straight chain orbranched chain alkyl having 1 to 6 carbon atoms, which is exemplified bymethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like, preferablymethyl, ethyl, propyl and isopropyl.

[0155] The lower alkoxy at R³ is preferably straight chain or branchedchain alkoxy having 1 to 6 carbon atoms, which is exemplified bymethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and thelike, preferably methoxy, ethoxy, propoxy and isopropoxy.

[0156] The “alkenyl”, in the alkenyl optionally having a substituent atR² and R⁴ is preferably straight chain or branched chain alkenyl having2 to 6 carbon atoms, which is exemplified by vinyl, 1-propenyl,2-propenyl, isopropenyl, allyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl and the like, preferably allyl, 2-butenyl, 3-butenyl,4-pentenyl, 2-propenyl and 2-methyl-1-propenyl. As the substituent,exemplified are lower alkoxy (as defined for lower alkoxy at R³),hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorine atom, bromineatom, iodine atom and fluorine atom), nitro, amino and the like. Whenalkenyl at R² or R⁴ is substituted, the number of the substituent ispreferably 1 or 2.

[0157] The “alkynyl” in the alkynyl optionally having a substituent atR² is preferably straight chain or branched chain alkynyl having 2 to 4carbon atoms, which is exemplified by ethynyl, 1-propynyl, 2-propynyl,1-methyl-2-propynyl and the like, preferably ethynyl and 2-propynyl. Asthe substituent, exemplified are lower alkoxy (as defined for loweralkoxy at R³), hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorineatom, bromine atom, iodine atom and fluorine atom), nitro, amino and thelike. When alkynyl at R² is substituted, the number of the substituentis preferably 1 or 2.

[0158] The “alkyl” in the alkyl optionally having a substituent at R²and R⁴ is preferably straight chain or branched chain alkyl having 1 to8 carbon atoms, which is exemplified by methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl, heptyl, octyl and the like, preferably methyl, ethyl,isobutyl, propyl, hexyl, pentyl and isopropyl. As the substituent,exemplified are lower alkoxy (as defined for lower alkoxy at R³),hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorine atom, bromineatom, iodine atom and fluorine atom), nitro, amino and the like. Whenalkyl at R² is substituted, the number of the substituent is preferably1 or 2.

[0159] The cycloalkyl at R² is preferably cycloalkyl having 3 to 8carbon atoms, which is exemplified by cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like,preferably cyclopropyl, cyclopentyl and cyclohexyl.

[0160] The cycloalkylalkyl at R² is that wherein cycloalkyl moiety ispreferably cycloalkyl having 3 to 8 carbon atoms and alkyl moiety ispreferably straight chain or branched chain alkyl having 1 to 3 carbonatoms. Examples thereof are cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,cyclooctylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl,2-cyclopentylethyl, 2-cyclohexylethyl, 2-cycloheptylethyl,2-cyclooctylethyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl,3-cyclopentylpropyl, 3-cyclohexylpropyl, 3-cycloheptylpropyl,3-cyclooctylpropyl, 1-cyclohexylethyl, 1-cyclohexylpropyl,2-cyclohexylpropyl and the like, preferably cyclohexylmethyl,2-cyclohexylethyl, cyclopentylmethyl and 2-cyclopentylethyl.

[0161] The aryl in the aryl optionally having a substituent at R², R⁴and Y is exemplified by phenyl, naphthyl and the like. As thesubstituent, exemplified are lower alkyl (as defined for lower alkyl atR¹, R³ and R⁵), lower alkoxy (as defined for lower alkoxy at R³),hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorine atom, bromineatom, iodine atom and fluorine atom), nitro, amino, acyl (e.g., formyl,acetyl, propanoyl etc.) and the like. When aryl at Y is substituted, thenumber of the substituent is preferably 1 or 2.

[0162] The arylalkyl optionally having a substituent at R² and R⁴ isexemplified by that wherein aryl moiety is preferably phenyl, naphthyland the like, and alkyl moiety is preferably straight chain or branchedchain alkyl having 1 to 3 carbon atoms. Examples of arylalkyl arebenzyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl,2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, 3-phenylpropyl,3-(1-naphthyl)propyl, 3-(2-naphthyl)propyl, 1-phenylethyl,2-phenylpropyl, 1-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl,1-(1-naphthyl)propyl, 1-(2-naphthyl)propyl, 2-(1-naphthyl)propyl,2-(2-naphthyl)propyl and the like, preferably benzyl, 3-phenylpropyl,1-naphthylmethyl and 2-naphthylmethyl. As the substituent, exemplifiedare lower alkyl (as defined for lower alkyl at R¹, R³ and R⁵), loweralkoxy (as defined for lower alkoxy at R³), hydroxy, carboxy,alkoxycarbonyl, halogen atom (chlorine atom, bromine atom, iodine atomand fluorine atom), nitro, amino, acyl (e.g., formyl, acetyl, propanoyletc.) and the like, preferably lower alkyl, lower alkoxy, halogen atomand acyl. When arylalkyl at Y is substituted, the number of thesubstituent is preferably 1 or 2.

[0163] The aromatic heterocycle in the aromatic heterocyclic residueoptionally having a substituent at Y is preferably a monocyclicheterocycle or a condensed heterocycle containing at least one heteroatom selected from the group consisting of oxygen atom, nitrogen atomand sulfur atom. The condensed heterocycle in the present invention hastwo rings and encompasses that having hetero atom(s) on the both rings.Preferable monocyclic heterocycle includes a 5- or 6-membered ring. Theheterocycle constituting the condensed heterocycle is preferably a 5- or6-membered ring. The ring without a hetero atom, which constitutes thecondensed heterocycle, is preferably a 5- or 6-membered ring. Examplesof the aromatic heterocyclic residue are monocyclic heterocyclic residuesuch as furyl, thienyl, pyridyl, imidazolyl, pyrazolyl, oxazolyl,isooxazolyl, thiazolyl, triazolyl, thiadiazolyl, oxadiazolyl,pyridazinyl, pyrimidinyl or pyrazinyl and the like; a condensedheterocyclic residue such as indolyl, isoindolyl, indolinyl,isoindolinyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, benzoxazinyl,benzothiazinyl, furo[2,3-b]pyridyl, thieno[2,3-b]pyridyl,naphthyridinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl and thelike, with preference given to pyridyl, oxazolyl, indolinyl,benzoxazolyl, thiazolyl, benzothiazolyl, indolyl, quinolyl andbenzofuranyl. As the substituent, exemplified are lower alkyl (asdefined for lower alkyl at R¹, R³ and R⁵), lower alkoxy (as defined forlower alkoxy at R³), hydroxy, carboxy, alkoxycarbonyl, halogen atom(chlorine atom, bromine atom, iodine atom and fluorine atom), nitro,amino aryl (e.g., phenyl, naphthyl and the like), heterocyclic residue(e.g., thienyl, pyridyl, furyl and the like), alkenyl (as defined foralkenyl at R² and R⁴), cycloalkyl (e.g., cyclopropyl etc.) and the like,preferably aryl, lower alkyl, carboxy, heterocyclic residue, alkenyl andcycloalkyl. When aromatic heterocyclic residue at Y is substituted, thenumber of the substituent is preferably 1 or 2.

[0164] The lower alkylene at B is preferably straight chain or branchedchain alkylene having 1 to 6 carbon atoms, which is exemplified bymethylene, ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, methylmethylene, 2,2-dimethyltrimethylene,2-ethyltrimethylene, 1-methyltetramethylene, 2-methyltetramethylene,3-methyltetramethylene, 3,3-dimethyltrimethylene,3,3-dimethyltetramethylene and the like, preferably ethylene,trimethylene and tetramethylene.

[0165] The heterocyclic moiety in the heterocyclic alkyl optionallyhaving a substituent at R² is as defined for the “aromatic heterocyclicresidue” in the “aromatic heterocyclic residue optionally having asubstituent” at Y. As the alkyl moiety, exemplified is straight chain orbranched chain alkyl having 1 to 3 carbon atoms. The specific examplesof the heterocyclic alkyl are 1-pyridylmethyl, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl; 1-(1-pyridyl)ethyl,1-(2-pyridyl)ethyl, 1-(3-pyridyl)ethyl, 1-(4-pyridyl)ethyl,2-(1-pyridyl)ethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl,2-(4-pyridyl)ethyl; 1-(1-pyridyl)propyl, 1-(2-pyridyl)propyl,1-(3-pyridyl)propyl, 1-(4-pyridyl)propyl, 2-(1-pyridyl)propyl,2-(2-pyridyl)propyl, 2-(3-pyridyl)propyl, 2-(4-pyridyl)propyl,3-(1-pyridyl)propyl, 3-(2-pyridyl)propyl, 3-(3-pyridyl)propyl,3-(4-pyridyl)propyl; 2-thienylmethyl, 3-thienylmethyl;1-(2-thienyl)ethyl, 1-(3-thienyl)ethyl, 2-(2-thienyl)ethyl,2-(3-thienyl)ethyl; 1-(2-thienyl)propyl, 1-(3-thienyl)propyl,2-(2-thienyl)propyl, 2-(3-thienyl)propyl, 3-(2-thienyl)propyl,3-(3-thienyl)propyl; and the like. The heterocyclic alkyl may besubstituted at the heterocyclic moiety. As the substituent, exemplifiedare lower alkyl (as defined for lower alkyl at R¹, R³ and R⁵), loweralkoxy (as defined for lower alkoxy at R³), hydroxy, carboxy,alkoxycarbonyl, halogen atom (chlorine atom, bromine atom, iodine atomand fluorine atom), nitro, amino and the like. When the heterocyclicmoiety is substituted, the number of the substituent is preferably 1 or2.

[0166] With regard to the heterocyclic residue optionally having asubstituent at R⁴, the heterocyclic moiety is the same as the “aromaticheterocyclic residue” in the “aromatic heterocyclic residue optionallyhaving a substituent” at Y, which is preferably pyridyl. Theheterocyclic residue may be substituted. As the substituent, exemplifiedare lower alkyl (as defined for lower alkyl at R¹, R³ and R⁵), loweralkoxy (as defined for lower alkoxy at R³), hydroxy, carboxy,alkoxycarbonyl, halogen atom (chlorine atom, bromine atom, iodine atomand fluorine atom), nitro, amino and the like. When the heterocyclicmoiety is substituted, the number of the substituent is preferably 1 or2.

[0167] The heterocyclic compound [I] and a pharmaceutically acceptablesalt thereof are preferably exemplified by the following.

[0168] A heterocyclic compound of the above-mentioned formula [I],wherein

[0169] (1) R¹ is hydrogen atom or lower alkyl,

[0170] R² is hydrogen atom, alkyl optionally having a substituent,cycloalkyl, cycloalkylalkyl, aryl optionally having a substituent,arylalkyl optionally having a substituent or —COR⁴ wherein R⁴ ishydrogen atom, alkyl optionally having a substituent, aryl optionallyhaving a substituent or arylalkyl optionally having a substituent,

[0171] R³ is hydrogen atom, lower alkyl or lower alkoxy,

[0172] A is a single bond or >N—R⁵ wherein R⁵ is hydrogen atom or loweralkyl,

[0173] B is lower alkylene, and

[0174] Y is aryl optionally having a substituent or an aromaticheterocyclic residue optionally having a substituent,

[0175] (2) R¹ is hydrogen atom or lower alkyl,

[0176] R² is hydrogen atom, alkyl, cycloalkylalkyl, arylalkyl optionallyhaving a substituent, alkenyl, alkynyl, heterocyclic alkyl or —COR⁴wherein R⁴ is alkyl, alkenyl or aryl,

[0177] R³ is hydrogen atom or lower alkoxy,

[0178] A is a single bond or >N—R⁵ wherein R⁵ is lower alkyl,

[0179] B is lower alkylene, and

[0180] Y is aryl or an aromatic heterocyclic residue optionally having asubstituent, or

[0181] (3) R¹ is hydrogen atom or lower alkyl,

[0182] R² is hydrogen atom, alkyl, cycloalkylalkyl, arylalkyl optionallyhaving a substituent or —COR⁴ wherein R⁴ is alkyl or aryl,

[0183] R³ is hydrogen atom,

[0184] A is a single bond or >N—R⁵ wherein R⁵ is lower alkyl,

[0185] B is lower alkylene, and

[0186] Y is an aromatic heterocyclic residue optionally having asubstituent and a pharmaceutically acceptable salt thereof.

[0187] In the formula [I], Y—A— is preferably

[0188] wherein R^(A) is isopropyl or tert-butyl,

[0189] R^(B) is isopropyl or tert-butyl, and

[0190] R^(C) is isopropyl, tert-butyl, phenyl, thiophen-2-yl,2-methylpropenyl or 3-butenyl; or

[0191] wherein R^(A) is isopropyl or tert-butyl,

[0192] R^(B) is isopropyl or tert-butyl,

[0193] R^(C) is isopropyl, tert-butyl, phenyl, thiophen-2-yl,2-methylpropenyl, 3-butenyl, cyclopropyl, 1-butenyl or2,2-dimethylpropyl, with particular preference given to

[0194] Preferable examples of the heterocyclic compound [I] and thepharmaceutically acceptable salt thereof are

[0195] (1)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0196] (2)2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0197] (3)2-acetyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0198] (4)2-methyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0199] (5)2-hexanoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0200] (6)2-hexyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0201] (7)2-isobutyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0202] (8)2-cyclohexylmethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0203] (9)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(3-phenylpropyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0204] (10)2-benzoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0205] (11)2-benzyl-7-[2-(N-methyl-N-(pyridin-2-yl)amino)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0206] (12)2-benzyl-7-[2-(5-ethyl-pyridin-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0207] (13)2-benzyl-7-[2-(indolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0208] (14) ethyl2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,

[0209] (15) methyl7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,

[0210] (16)2-(4-methoxybenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0211] (17) ethyl2-(4-methoxybenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,

[0212] (18)2-(4-methylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0213] (19) ethyl2-(4-methylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,

[0214] (20)2-benzyl-7-[2-(6-carboxyindolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, and

[0215] (21)2-(4-fluorobenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, and pharmaceutically acceptable salt thereof. Besides theabove-mentioned, preferred are

[0216] (22)2-(2,2-dimethylpropionyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0217] (23)2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0218] (24)2-benzyl-7-[2-(5-methyl-2-tert-butyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0219] (25)2-benzyl-7-[2-(5-methyl-2-(thiophen-2-yl)oxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0220] (26)2-benzyl-7-[2-(5-methyl-2-isopropyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0221] (27)2-butyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0222] (28)2-benzyl-7-{2-[5-methyl-2-(2-methylpropenyl)oxazol-4-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0223] (29)2-benzyl-7-{2-[2-(3-butenyl)-5-methyloxazol-4-yl]-ethoxy}-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0224] (30)2-allyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0225] (31)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(2-propynyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0226] (32)2-(2-butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0227] (33)2-benzyl-7-[(indolin-3-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0228] (34)2-(3-butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0229] (35)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-pentanoyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0230] (36)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(4-pentenoyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0231] (37)2-(3-methyl-2-butenoyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0232] (38)2-(3,3-dimethylbutyryl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0233] (39)2-benzyl-7-methoxy-6-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3RS)-carboxylicacid,

[0234] (40)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0235] (41)2-benzyl-7-(3-methyl-3-phenylbutoxy)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0236] (42)2-benzyl-7-(3,3-dimethyl-4-phenylbutoxy)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0237] (43)2-benzyl-7-(2-isopropylbenzoxazol-6-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0238] (44)2-benzyl-7-(2-tert-butylbenzoxazol-6-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0239] (45)2-benzyl-7-(2-tert-butylbenzoxazol-5-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0240] (46)7-(2-tert-butylbenzoxazol-6-yl)methoxy-2-(2,2-dimethylpropyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, and

[0241] (47)2-benzyl-7-(2-isopropylbenzoxazol-5-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, and pharmaceutically acceptable salts thereof.

[0242] In addition to the above-mentioned, the following heterocycliccompound [I] and pharmaceutically acceptable salts thereof arepreferable.

[0243] (48)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0244] (49)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-[(pyridin-2-yl)carbonyl]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0245] (50) methyl2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,

[0246] (51)2-benzyl-7-[2-(2-cyclopropyl-5-methyloxazol-4-yl)-ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0247] (52)2-(3-methyl-2-butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, p0 (53)2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-tert-butyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0248] (54)2-benzyl-7-[2-(1-butenyl)-5-methyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0249] (55)2-benzyl-7-[2-(2,2-dimethylpropyl)-5-methyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0250] (56) ethyl2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,

[0251] (57)7-(benzofran-2-ylmethoxy)-2-benzyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0252] (58)2-isobutyryl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0253] (59)7-[2-(benzofran-2-yl)ethoxy]-2-benzyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0254] (60)7-[2-(5-ethylpyridin-2-yl)ethoxy]-2-hexanoyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0255] (61)2-carboxymethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0256] (62)2-[3-(methoxycarbonyl)propionyl]-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0257] (63)2-[3-(ethoxycarbonyl)propyl]-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0258] (64)2-benzyl-6-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3RS)-carboxylicacid,

[0259] (65)2-(3-acetylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0260] (66)2-(2-acetylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid,

[0261] (67)2-benzyl-7-[(5-methyl-2-phenyloxazol-4-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid.

[0262] Since the heterocyclic compound [I] has an asymmetric carbon atthe 3-position of the 1,2,3,4-tetrahydroisoquinoline ring, it includesvarious stereoisomers. The most preferable configuration is

[0263] wherein R¹, R², R³, Y, A and B are as defined above.

[0264] The heterocyclic compound [I] can be converted to apharmaceutically acceptable salt as necessary.

[0265] When the heterocyclic compound [I] has a basic group, an acidaddition salt can be formed. The acid used for forming the acid additionsalt is not subject to any particular limitation as long as it can forma salt with a basic moiety and it is a pharmaceutically acceptable acid.Examples of the acid include inorganic acids such as hydrochloric acid,sulfuric acid, phosphoric acid, nitric acid and the like, and organicacids such as oxalic acid, fumaric acid, maleic acid, citric acid,tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and thelike, and the like.

[0266] When the heterocyclic compound [I] has an acidic group (e.g.,carboxyl group and the like), a salt such as an alkali metal salt (e.g.,sodium salt, potassium salt and the like), an alkaline earth metal salt(e.g., calcium salt, magnesium salt and the like) or an organic basesalt (e.g., triethylamine salt, dicyclohexylamine salt, pyridine saltand the like) and the like may be formed.

[0267] The heterocyclic compound [I] and the pharmaceutically acceptablesalt thereof can be produced according to any of the followingProduction Methods.

[0268] wherein R¹, R³, A, B and Y are as defined above, R⁶ is hydrogenatom, alkyl optionally having a substituent, cycloalkyl,cycloalkylalkyl, aryl optionally having a substituent, arylalkyloptionally having a substituent, alkenyl optionally having asubstituent, alkynyl optionally having a substituent, heterocyclic alkyloptionally having a substituent, —COR⁴ (R⁴ is as defined above) oramino-protecting group, and X is hydroxy, halogen atom (fluorine atom,chlorine atom, bromine atom or iodine atom), or a leaving group such asalkanesulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy,propanesulfonyloxy, trifluoromethanesulfonyloxy and the like),arylsulfonyloxy (e.g., phenylsulfonyloxy, tolylsulfonyloxy and the like)and the like.

[0269] In Production Method 1, the compound of formula [Ia] (alsoreferred to as compound [Ia]) is synthesized by the reaction of thecompound of the formula [II] (also referred to as compound [II]) withthe compound of the formula [III] (also referred to as compound [III]).

[0270] The “alkyl optionally having a substituent”, “cycloalkyl”,“cycloalkylalkyl”, “aryl optionally having a substituent”, “arylalkyloptionally having a substituent”, “alkenyl optionally having asubstituent”, “alkynyl optionally having a substituent” and“heterocyclic alkyl optionally having a substituent” at R⁶ are asdefined for R².

[0271] Examples of the amino-protecting group at R⁶ are formyl,monochloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl,methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl,p-nitrobenzyloxycarbonyl, diphenylmethyloxycarbonyl,methoxymethylcarbonyl, methoxymethyloxycarbonyl, trimethylsilyl,2,2,2-trichloroethoxycarbonyl, 2-methylsulfonylethyloxycarbonyl,tert-butoxycarbonyl (hereinafter to be referred to as Boc), trityl andthe like.

[0272] Production Method 1-a: When X is hydroxy, Production Method 1comprises a dehydrating reaction such as Mitsunobu Reaction (Reagentsfor Organic Synthesis, Fisher & Fisher, Vol. 6, 645) and the like. Thereaction is generally carried out in a solvent with an azo compound andphosphine. As the azo compound, exemplified are di(C₁-C₄ alkyl)azodicarboxylate (e.g., diethyl azodicarboxylate and the like),azodicarboxamide (e.g., 1,1′-(azodicarbonyl)dipiperidine and the like)and the like. As the phosphine, exemplidfied are triarylphosphine (e.g.,triphenylphosphine and the like), tri(C₁-C₄alkyl)phosphine (e.g.,tributylphosphine and the like), and the like.

[0273] As the solvent used in the Production Method 1-a, exemplified aredioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride,ethylene chloride, benzene, toluene, xylene, ethyl acetate,N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and thelike; and a mixture thereof and the like, but the solvent is not limitedas far as it does not adversely influence the reaction.

[0274] The amount of the compound [II] used in the Production Method 1-ais not subject to any particular limitation. It is used in an amount ofgenerally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [III]. Theazo compound and phosphine are respectively used in an amount ofgenerally 1-3 mol, preferably 1-1.5 mol, per 1 mol of compound [III].

[0275] While the reaction conditions such as reaction temperature andreaction time and the like in Production Method 1-a vary depending onthe reagent, solvent and the like to be used in this reaction, thereaction generally proceeds at a temperature of from −30° C. to 50° C.for 30 min to about a dozen hours.

[0276] Production Method 1-b: When X is halogen atom or leaving groupsuch as alkanesulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy,propanesulfonyloxy, trifluoromethanesulfonyloxy and the like),arylsulfonyloxy (e.g., phenylsulfonyloxy, tolylsulfonyloxy and the like)and the like, Production Method 1-b is performed in a solvent similar tothat used in the Production Method 1-a and in the presence of a base.

[0277] The base used in the Production Method 1-b is exemplified by, butnot particulary limited to, inorganic base such as alkali metalcarbonate (e.g., sodium carbonate, potassium carbonate, sodiumhydrogencarbonate, potassium hydrogencarbonate and the like), alkalimetal hydroxide (e.g., sodium hydroxide, potassium hydroxide and thelike), metal hydride compound (e.g., sodium hydride, potassium hydride,calcium hydride and the like) and the like; organic base such as alkalimetal alkoxide (e.g., sodium methoxide, sodium ethoxide, potassiumtert-butoxide and the like), amines (e.g., triethylamine,diisopropylethylamine and the like) and the like.

[0278] The amount of the compound [II] used in the Production Method 1-bis not subject to any particular limitation. It is used in an amount ofgenerally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [III]. Thebase is used in an amount of generally 1-5 mol, preferably 1-3 mol, per1 mol of compound [III].

[0279] While the reaction conditions such as reaction temperature andreaction time and the like in Production Method 1-b vary depending onthe reagent, solvent and the like to be used in this reaction, thereaction generally proceeds at a temperature of from −30° C. to 150° C.for 30 min to about a dozen hours.

[0280] In the Production Method 1, R¹ of compound [III] is preferablylower alkyl. In this case, compound [Ia] wherein R¹ is lower alkyl isobtained, and this compound may be led to the compound [Ia] wherein R¹is hydrogen atom, by hydrolysis according to a method known per se.

[0281] In the Production Method 1, when R⁶ of compound [III] isamino-protecting group, compound [Ia] wherein R⁶ is amino-protectinggroup is obtained. This compound may be led to the compound [Ia] whereinR⁶ is hydrogen atom, by deprotection according to a method known per se.

[0282] wherein R¹, R³, A, B and Y are as defined above, R⁷ isamino-protecting group, R⁸ is alkyl optionally having a substituent,cycloalkyl, cycloalkylalkyl, aryl optionally having a substituent,arylalkyl optionally having a substituent, alkenyl optionally having asubstituent, alkynyl optionally having a substituent or heterocyclicalkyl optionally having a substituent, and U is halogen atom (fluorineatom, chlorine atom, bromine atom, iodine atom), or a leaving group suchas alkanesulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy,propanesulfonyloxy, trifluoromethanesulfonyloxy and the like),arylsulfonyloxy (e.g., phenylsulfonyloxy, tolylsulfonyloxy and the like)and the like.

[0283] In Production Method 2, the amino-protecting group R⁷ of acompound of the formula [Ib] (also referred to as compound [Ib]) iseliminated by a method known per se to give a compound of the formula[Ic] (also referred to as compound [Ic]), which is then reacted with acompound of the formula [V] (also referred to as compound [V]), wherebya compound of the formula [Id] (also referred to as compound [Id]) isproduced.

[0284] The “alkyl optionally having a substituent”, “cycloalkyl”,“cycloalkylalkyl”, “aryl optionally having a substituent”, “arylalkyloptionally having a substituent”, “alkenyl optionally having asubstituent”, “alkynyl optionally having a substituent” and“heterocyclic alkyl optionally having a substituent” at R⁸ are asdefined for R².

[0285] The amino-protecting group at R⁷ is as defined for R⁶.

[0286] In the Production Method 2, compound [Ic] is reacted withcompound [V] in a solvent that does not inhibit the reaction, such asdioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride,ethylene chloride, benzene, toluene, xylene, ethyl acetate,N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and thelike; and a mixture thereof and the like, in the presence of a base, togive compound [Id].

[0287] In the Production Method 2, the base used for the reaction ofcompound [Ic] with compound [V] is exemplified, but not particularylimited to, inorganic base such as alkali metal carbonate (e.g., sodiumcarbonate, potassium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate and the like), alkali metal hydroxide (e.g., sodiumhydroxide, potassium hydroxide and the like), metal hydride compound(e.g., sodium hydride, potassium hydride and calcium hydride and thelike) and the like; and organic base such as alkali metal alkoxide(e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide andthe like), amines (e.g., triethylamine, diisopropylethylamine and thelike) and the like.

[0288] The amount of the compound [V] used in the Production Method 2 isgenerally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [Ic]. Thebase is used in an amount of generally 1-5 mol, preferably 1-3 mol, per1 mol of compound [Ic].

[0289] While the reaction conditions such as reaction temperature andreaction time and the like for the reaction of compound [Ic] withcompound [V] in the Production Method 2 vary depending on the reagent,solvent and the like to be used in this reaction, the reaction generallyproceeds at a temperature of from −30° C. to 150° C. for 30 min to abouttwo dozen hours.

[0290] In the Production Method 2, R¹ of compound [Ib] is preferablylower alkyl. In this case, compound [Id] wherein R¹ is lower alkyl isobtained, and this compound may be led to the compound [Id] wherein R¹is hydrogen atom, by hydrolysis according to a method known per se.

[0291] wherein R¹, R³, R⁴, A, B and Y are as defined above.

[0292] In Production Method 3, a compound of the formula [Ie] (alsoreferred to as compound [Ie]) is synthesized by reacting compound [Ic]with a compound of the formula [VI] (also referred to as compound [VI]).

[0293] In the Production Method 3, compound [VI] may be used not only inthe form of a free acid, but also in the form of a salt (e.g., sodiumsalt, potassium salt, calcium salt, triethylamine salt, pyridine saltand the like) or as a reactive derivative (e.g., acid halide such asacid chloride, acid bromide and the like; acid anhydride; mixed acidanhydride with substituted phosphoric acid such as dialkyl phosphate andthe like, and alkyl carbonate such as monoethyl carbonate and the like;reactive amide which is amide with imidazole and the like; ester such ascyanomethyl ester and 4-nitrophenyl ester and the like), and the like.

[0294] In the Production Method 3, when the compound [VI] is used in theform of a free acid or a salt, this reaction is preferably carried outin the presence of a condensing agent. As the condensing agent, adehydrating agent such as carbodiimide compound (e.g.,N,N′-dicyclohexylcarbodiimide,1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide,N-cyclohexyl-N′-morpholinoethylcarbodiimide,N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide and the like),azolide compound (e.g., N,N′-carbonyldiimidazole,N,N′-thionyldiimidazole and the like) and the like, and the like can beused. The condensing agent is used in an amount of generally 1-5 mol,preferably 1-3 mol, per 1 mol of compound [Ic]. It is considered that,when a condensing agent is used, compound [VI] becomes a reactivederivative and proceeds to the reaction.

[0295] The Production Method 3 is generally performed in a solvent inertto the reaction. As the solvent, exemplified are acetone, dioxane,acetonitrile, chloroform, benzene, methylene chloride, ethylenechloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide,pyridine, water and a mixed solvent thereof. In the Production Method 3,a base such as triethylamine, pyridine, 4-dimethylaminopyridine,potassium carbonate and the like can be used. When the base is used, itis used in an amount of generally 1-5 mol, preferably 1-3 mol, per 1 molof compound [Ic].

[0296] In Production Method 3, compound [VI] is used in an amount ofgenerally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [Ic].

[0297] While the reaction conditions such as reaction temperature andreaction time and the like in the reaction of compound [VI] withcompound [Ic] in the Production Method 3 vary depending on the reagent,solvent and the like to be used in this reaction, the reaction generallyproceeds at a temperature of from −30° C. to 150° C. for 10 min to abouta dozen hours.

[0298] In the Production Method 3, compound [Ie′] is obtained byreacting compound [VI] with compound [Ic], isolating and reducing theresulting compound [Ie]. This reduction reaction is carried out in asolvent that does not adversely influence the reaction (e.g., water,methanol, ethanol, dioxane, acetonitrile, tetrahydrofuran, chloroform,methylene chloride, ethylene chloride, benzene, toluene, xylene, ethylacetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, a mixture thereof and the like) in the presence of a reducingagent.

[0299] The reducing agent used in this reduction is exemplified by metalhydride complex (e.g., lithium aluminum hydride, sodium cyanoborohydride(NaBH₃CN), sodium borohydride and the like), borane and the like. Theagent is not subject to any particular limitation as long as it isgenerally used for reducing a carbonyl group to a methylene group. Thereducing agent is used in an amount of generally 1-5 mol, preferably 1-3mol, per 1 mol of compound [Ie].

[0300] While the reaction conditions such as reaction temperature andreaction time and the like in the reduction reaction vary depending onthe reagent, solvent and the like to be used in this reaction, thereaction generally proceeds at a temperature of from −30° C. to 150° C.for 30 min to about a dozen hours.

[0301] wherein R¹, R², R³, R⁵, B, X, Y and U are as defined above, andR¹⁰ is an amino-protecting group.

[0302] The amino-protecting group at R¹⁰ is as defined for R⁶.

[0303] Production Method 4 is intended for the heterocyclic compound [I]wherein A is >N—R⁵. In this method, compound of the formula [VII] (alsoreferred to as compound [VII]) is reacted with compound of the formula[VIII] (also referred to as compound [VIII]) in the same manner as inProduction Method 1 to give a compound of the formula [IX] (alsoreferred to as compound [IX]), and the amino-protecting group at R₁₀ ofthe compound [IX] is eliminated by a method known per se to give acompound of the formula [X] (also referred to as compound [X]), which isthen reacted with a compound of the formula [XI] (also referred to ascompound [XI]), whereby a compound of the formula [If] (also referred toas compound [If]) is produced.

[0304] The reaction of compound [X] with compound [XI] in ProductionMethod 4 is carried out in a solvent that does not adversely influencethe reaction in the presence of a base. As the solvent, exemplified aredioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride,ethylene chloride, benzene, toluene, xylene, ethyl acetate,N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and thelike; and a mixture thereof. When compound [XI] can be used as asolvent, it can be used as a solvent.

[0305] The base used in the reaction of compound [X] with compound [XI]in the Production Method 4 is exemplified, but not particulary limitedto, inorganic base such as alkali metal carbonate (e.g., sodiumcarbonate, potassium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate and the like), alkali metal hydroxide (e.g., sodiumhydroxide, potassium hydroxide and the like), metal hydride compound(e.g., sodium hydride, potassium hydride, calcium hydride and the like)and the like; and organic base such as alkali metal alkoxide (e.g.,sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like)and amines (e.g., triethylamine, diisopropylethylamine and the like) andthe like. The base is used in an amount of generally 1-5 mol, preferably1-3 mol, per 1 mol of compound [X].

[0306] In Production Method 4, compound [XI] is used in a proportion ofgenerally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [X].

[0307] While the reaction conditions such as reaction temperature andreaction time and the like in the reaction of compound [X] with compound[XI] in the Production Method 4 vary depending on the reagent, solventand the like to be used in this reaction, the reaction generallyproceeds at a temperature of from −30° C. to 150° C. for 30 min to abouta dozen hours.

[0308] wherein R¹, R³, A, B and Y are as defined above, R⁹ is such agroup as makes a group of the formula:—CH₂—R⁹ alkyl optionally having asubstituent, cycloalkylalkyl, arylalkyl optionally having a substituent,alkenyl optionally having a substituent, alkynyl optionally having asubstituent or heterocyclic alkyl optionally having a substituent.

[0309] In Production Method 5, compound [Ic] is reacted with a compoundof the formula [XII] (also referred to as compound [XII]), whereby acompound of the formula [Ig] (also referred to as compound [Ig]) isproduced.

[0310] In a group of the formula: —CH₂—R⁹, the “alkyl optionally havinga substituent”, “cycloalkylalkyl”, “arylalkyl optionally having asubstituent”, “alkenyl optionally having a substituent”, “alkynyloptionally having a substituent” and “heterocyclic alkyl optionallyhaving a substituent” are as defined for R². In Production Method 5,compound [Ic] and compound [XII] are condensed in a solvent which doesnot inhibit the reaction (e.g., water, methanol, ethanol, dioxane,acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylenechloride, benzene, toluene, xylene, ethyl acetate,N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, amixture thereof and the like) in the presence of a reducing agent.

[0311] The reducing agent used in the Production Method 5 is not subjectto any particular limitation, and is exemplified by metal hydridecomplex (e.g., lithium aluminum hydride, sodium cyanoborohydride(NaBH₃CN), sodium borohydride and the like), borane and the like.

[0312] In Production Method 5, compound [XII] is used in an amount ofgenerally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [Ic]. Thereducing agent is used in an amount of generally 1-5 mol, preferably 1-3mol, per 1 mol of compound [Ic].

[0313] While the reaction conditions such as reaction temperature andreaction time and the like in Production Method 5 vary with the reagent,solvent and the like to be used in this reaction, the reaction generallyproceeds at a temperature of from −30° C. to 150° C. for 30 min to abouta dozen hours.

[0314] The heterocyclic compound [I] obtained in the above-mentionedProduction Methods 1-5 may be isolated by a conventional method, and,where necessary, purified by a conventional method such asrecrystallization, preparative thin-layer chromatography, columnchromatography and the like. The compound can be also purified into asalt as necessary.

[0315] The heterocyclic compound [I] may be converted to apharmaceutically acceptable salt thereof by a method known per se.

[0316] The pharmaceutical composition comprising the heterocycliccompound [I] or a pharmaceutically acceptable salt thereof of thepresent invention may contain an additive and the like. As an additive,exemplified are excipient (e.g., starch, lactose, sugar, calciumcarbonate, calcium phosphate and the like), binder (e.g., starch, gumarabic, carboxymethylcellulose, hydroxypropylcellulose, crystallinecellulose and the like), lubricant (e.g., magnesium stearate, talc andthe like), disintegrator (e.g., carboxymethylcellulose calcium, talc andthe like), and the like.

[0317] The above-mentioned components are mixed to give a preparationfor oral administration such as capsule, tablet, powder, granule, drysyrup and the like, or a preparation for parenteral administration suchas injection, suppository and the like, according to a method known perse.

[0318] While the dose of the heterocyclic compound [I] or apharmaceutically acceptable salt thereof may vary according to theadministration subject, symptom and other factors, when it is orallyadministered to an adult patient with, for example, diabetes, diabeticcomplications or hyperlipidemia, the single dose is approximately 1-500mg/kg body weight, which is administered 1 to 3 times a day.

[0319] The heterocyclic compound [I] and a pharmaceutically acceptablesalt of the present invention show a superior hypoglycemic action, ablood hypolipidemic action, an insulin resistance-improving action and aPPAR activating action in mammals (human, cattle, horse, dog, cat, rat,mouse, hamster and the like), and are useful as a hypoglycemic agent, ahypolipidemic agent, an insulin resistance improver, a therapeutic agentof diabetes, a therapeutic agent of diabetic complication, a glucosetolerance improver, an anti-atherosclerosis agent, an anti-obesityagent, an antiinflammatory agent, an agent for the prophylaxis ortreatment of PPAR-mediated disease and an agent for the prophylaxis ortreatment of syndrome X. To be specific, the heterocyclic compound [I]and a pharmaceutically acceptable salt of the present invention areuseful for the prophylaxis or treatment of diabetes, diabeticcomplications, hyperlipidemia, atherosclerosis, hyperglycemia, diseasescaused by insulin resistant impaired glucose tolerance, diseases causedby insulin resistance, obesity, inflammation, PPAR-mediated disease andsyndrome X.

EXAMPLES

[0320] The present invention is explained in detail by referring to thefollowing examples. The present invention is not limited by theseexamples in any way.

Example 1 Sodium7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0321] (1) Ethyl2-tert-butoxycarbonyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(1.50 g) and 2-(5-methyl-2-phenyloxazol-4-yl)ethyl methanesulfonate(2.50 g) were dissolved in N,N-dimethylformamide (20 ml). Thereto wasadded potassium carbonate (2.0 g) and the mixture was stirred at 80° C.for 5 hr. Ethyl acetate (100 ml) was added to the reaction mixture, andthe mixture was washed with water (100 ml) and saturated brine (50 ml)and dried over Na₂SO₄. Ethyl acetate was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give ethyl2-tert-butoxycarbonyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(1.62 g).

Ethyl2-tert-butoxycarbonyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

[0322] IR v(neat) cm-⁻¹; 2978, 2930, 1738, 1699, 1614, 1587.

[0323]¹H-NMR (CDCl₃) δ (ppm);

[0324] 1.29 (3H, t, J=7.0 Hz), 1.46, 1.50 (9H, s, s), 2.36 (3H, s), 2.95(2H, t, J=6.8 Hz), 2.90-3.30 (2H, m), 4.00-4.40 (4H, m), 4.51, 4.61 (2H,s, s), 4.70-4.90, 5.00-5.20 (1H, m, m), 6.60-6.90 (2H, m), 7.12 (1H, d,J=8.4 Hz), 7.30-7.55 (3H, m), 7.90-8.15 (2H, m).

[0325] (2) The compound (5.2 g) obtained in (1) above was dissolved informic acid (20 ml). Thereto was added a 8.78N hydrogen chloridesolution (6.0 ml) in 2-propanol under ice-cooling, and the mixture wasstirred at room temperature for 10 min. Ethyl acetate (100 ml) was addedto the reaction mixture, and the mixture was neutralized with saturatedaqueous sodium hydrogencarbonate solution and separated into two layers.The obtained ethyl acetate layer was washed with saturated brine (50 ml)and dried over Na₂SO₄. Ethyl acetate was evaporated under reducedpressure to give ethyl7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(3.6 g).

Ethyl7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

[0326] IR v (nujol) cm⁻¹; 3476, 1742, 1639, 1611, 1553.

[0327]¹H-NMR (CDCl₃) δ (ppm);

[0328] 1.29 (3H, t, J=7.0 Hz), 2.02 (1H, s), 2.36 (3H, s), 2.80-3.10(4H, m), 3.50-3.80 (1H, m), 4.00-4.40 (6H, m), 6.50-6.80 (2H, m), 7.00(1H, d, J=8.4 Hz), 7.30-7.50 (3H, m), 7.90-8.10 (2H, m).

[0329] (3) The compound (1.11 g) obtained in (2) above was dissolved inmethanol (20 ml). Thereto was added 1N aqueous sodium hydroxide solution(3.0 ml) and the mixture was stirred at room temperature for 2 hr. Thesolvent was evaporated under reduced pressure. Water (5 ml) was added tothe obtained crystalline residue, and the crystals were collected byfiltration to give the title compound (0.92 g).

[0330] IR v (nujol) cm⁻¹; 3427, 1589, 1504.

[0331]¹H-NMR (DMSO-d₆) δ (ppm);

[0332] 2.35 (3H, s), 2.60-3.10 (6H, m), 3.86 (2H, br-s), 4.14 (2H, t,J=6.6 Hz), 6.50-6.80 (2H, m), 6.94 (1H, d, J=8.1 Hz), 7.40-7.60 (3H, m),7.75-8.05 (2H, m).

EXAMPLE 22-Benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0333] (1) The compound (1.40 g) obtained in Example 1(2) was dissolvedin N,N-dimethylformamide (20 ml). Thereto was added sodium hydride (160mg, 60% suspension in oil) under ice-cooling, and the mixture wasstirred at room temperature for 20 min. To the obtained mixture wasdropwise added benzyl bromide (0.40 ml), and the mixture was stirredfurther at the same temperature for 1 hr. Ethyl acetate (50 ml) wasadded to the reaction mixture, and the mixture was washed with water (50ml) and saturated brine (30 ml) and dried over Na₂SO₄. Ethyl acetate wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give ethyl2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(1.38 g).

Ethyl2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

[0334] IR v (nujol) cm⁻¹; 1728, 1639, 1614, 1551.

[0335]¹H-NMR (CDCl₃) δ (ppm);

[0336] 1.21 (3H, t, J=7.0 Hz), 2.34 (3H, s), 2.92 (2H, t, J=7.0 Hz),3.05-3.20 (2H, m), 3.60-4.00 (5H, m), 4.12 (2H, q, J=7.0 Hz), 4.16 (2H,t, J=7.0 Hz), 6.51 (1H, d, J=2.0 Hz), 6.68 (1H, dd, J=2.0, 8.4 Hz), 6.99(1H, d, J=8.4 Hz), 7.30-7.50 (8H, m), 7.80-8.10 (2H, m).

[0337] (2) The compound (8.20 g) obtained in (1) above was dissolved in80 ml of a mixed solution of tetrahydrofuran-methanol (3:1). Thereto wasadded 2N aqueous lithium hydroxide solution (42 ml), and the mixture wasstirred at 50° C. for 2 hr. The solvent was evaporated under reducedpressure, and the obtained residue was acidified with citric acid. Theprecipitated crystals were collected by filtration. The obtained crudecrystals (9.0 g) were recrystallized from methanol to give the titlecompound (6.33 g).

[0338] IR v (nujol) cm⁻¹; 1638, 1501.

[0339]¹H-NMR (DMSO-d₆) δ (ppm);

[0340] 2.33 (3H, s), 2.65-3.30 (4H, m), 3.50-4.00 (5H, m), 4.00-6.20(1H, br), 4.13 (2H, t, J=7.0 Hz), 6.59 (1H, br-s), 6.68 (1H, br-d, J=8.4Hz), 7.01 (1H, d, J=8.4 Hz), 7.32 (5H, s), 7.35-7.70 (3H, m), 7.85-8.10(2H, m).

EXAMPLE 32-Acetyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0341] (1) The compound (800 mg) obtained in Example 1(2) was dissolvedin methylene chloride (8.0 ml). Thereto was added acetic anhydride (0.23ml) under ice-cooling, and the mixture was stirred at room temperaturefor 10 min. Ethyl acetate (30 ml) was added to the reaction mixture, andthe mixture was neutralized with saturated aqueous sodiumhydrogencarbonate solution, and then the two layers were separated. Theobtained organic layer was washed with saturated brine (10 ml) and driedover Na₂SO₄. The solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive ethyl2-acetyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(873 mg).

Ethyl2-acetyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

[0342] IR v (nujol) cm⁻¹; 1732, 1651, 1555.

[0343]¹H-NMR (CDCl₃) δ (ppm);

[0344] 1.12 (3H, t, J=7.0 Hz), 2.13, 2.21 (3H, s, s), 2.36 (3H, s), 2.95(2H, t, J=6.6 Hz), 3.05-3.30 (2H, m), 4.04 (2H, q, J=7.0 Hz), 4.22 (2H,t, J=6.6 Hz), 4.62 (2H, s), 5.45 (1H, dd, J=4.0, 5.7 Hz), 6.55-6.85 (2H,m), 7.04 (1H, d, J=8.2 Hz), 7.30-7.50 (3H, m), 7.85-8.10 (2H, m).

[0345] (2) The compound (800 mg) obtained in (1) above was dissolved in5.0 ml of a mixed solution of tetrahydrofuran-methanol (3:1). Theretowas added 1N aqueous lithium hydroxide solution (3.0 ml), and themixture was stirred at room temperature for 30 min. The solvent wasevaporated under reduced pressure, and the obtained residue wasacidified with citric acid. The precipitated crystals were collected byfiltration to give the title compound (668 mg).

[0346] IR v (nujol) cm⁻¹; 3400, 1732, 1641, 1612, 1555.

[0347]¹H-NMR (CDCl₃) δ (ppm);

[0348] 2.10, 2.17 (3H, s, s), 2.32 (3H, s), 2.70-3.30 (4H, m), 3.90-4.20(2H, m), 4.30-4.90 (2H, m), 5.35-5.60 (1H, m), 6.50-6.80 (2H, m), 7.03(1H, d, J=8.1 Hz), 7.30-7.60 (3H, m), 7.80-8.10 (2H, m).

Example 42-Methyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0349] (1) The compound (1.0 g) obtained in Example 1(2) was dissolvedin methanol (10 ml). Thereto were added formalin (0.4 ml) and sodiumcyanoborohydride (310 mg), and the mixture was stirred at roomtemperature for 1 hr. Methanol was evaporated under reduced pressure.Ethyl acetate (20 ml) was added to the obtained residue, and the mixturewas washed with water (20 ml) and saturated brine (10 ml) and dried overNa₂SO₄. Ethyl acetate was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive ethyl2-methyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(1.08 g).

Ethyl2-methyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

[0350] IR v (neat) cm⁻¹; 2926, 2874, 1732, 1641, 1614.

[0351]¹H-NMR (CDCl₃) δ (ppm);

[0352] 1.25 (3H, t, J=7.0 Hz), 2.35 (3H, s), 2.50 (3H, s), 2.94 (2H, t,J=6.8 Hz), 3.02 (2H, d, J=6.0 Hz), 3.45 (1H, t, J=6.0 Hz), 3.64 (1H, d,J=15.6 Hz), 3.98 (1H, d, J=15.6 Hz), 4.17 (2H, q, J=7.0 Hz), 4.20 (2H,t, J=6.6 Hz), 6.56 (1H, d, J=2.0 Hz), 6.70 (1H, dd, J=2.0, 8.4 Hz), 6.98(1H, d, J=8.4 Hz), 7.30-7.50 (3H, m), 7.85-8.10 (2H, m).

[0353] (2) The compound (1.08 g) obtained in (1) above was dissolved in10 ml of a mixed solution of tetrahydrofuran-methanol (3:1). Thereto wasadded 1N aqueous lithium hydroxide solution (7.5 ml), and the mixturewas stirred at room temperature for 1 hr. The solvent was evaporatedunder reduced pressure, and the obtained residue was acidified withcitric acid. The precipitated crystals were collected by filtration togive the title compound (0.74 g).

[0354] IR v (nujol) cm⁻¹; 1616, 1555, 1541, 1506.

[0355]¹H-NMR (DMSO-d₆) δ (ppm);

[0356] 2.36 (3H, s), 2.55 (3H, s), 2.70-3.10 (4H, m), 3.40-3.60 (1H, m),3.70-4.30 (4H, m), 6.60-6.80 (2H, m), 7.05 (1H, d, J=8.6 Hz), 7.35-7.65(3H, m), 7.75-8.10 (2H, m).

EXAMPLE 52-Hexanoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0357] (1) The compound (1.0 g) obtained in Example 1(2) was dissolvedin methylene chloride (10 ml). Thereto were added hexanoyl chloride(0.41 ml) and triethylamine (0.51 ml) under ice-cooling, and the mixturewas stirred at the same temperature for 10 min. Ethyl acetate (70 ml)was added to the reaction mixture, and the mixture was washed with 10%aqueous citric acid solution (50 ml), saturated aqueous sodiumhydrogencarbonate solution (50 ml) and then saturated brine (50 ml) anddried over Na₂SO₄. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive ethyl2-hexanoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(1.02 g).

Ethyl2-hexanoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

[0358] IR v (nujol) cm⁻¹; 1736, 1653, 1587.

[0359]¹H-NMR (CDCl₃) δ (ppm);

[0360] 0.70-1.90 (12H, m), 2.20-2.60 (2H, m), 2.36 (3H, s), 2.95 (2H, t,J=6.8 Hz), 3.10-3.20 (2H, m), 4.04 (2H, q, J=7.0 Hz), 4.22 (2H, t, J=7.0Hz), 4.63 (2H, s), 5.45 (1H, dd, J=4.0, 5.4 Hz), 6.60-6.90 (2H, m), 7.04(1H, d, J=8.1 Hz), 7.30-7.50 (3H, m), 7.80-8.10 (2H, m).

[0361] (2) The compound (1.02 g) obtained in (1) above was dissolved in10 ml of a mixed solution of tetrahydrofuran-methanol (3:1). Thereto wasadded 1N aqueous lithium hydroxide solution (6.0 ml), and the mixturewas stirred at room temperature for 4 hr. The solvent was evaporatedunder reduced pressure, and the obtained residue was acidified withcitric acid. The precipitated crystals were collected by filtration togive the title compound (0.56 g).

[0362] IR v (nujol) cm⁻¹; 1742, 1641, 1612, 1572.

[0363]¹H-NMR (CDCl₃) δ (ppm);

[0364] 0.88 (3H, br-t, J=6.0 Hz), 1.10-1.90 (6H, m), 2.32 (3H, s),2.30-2.50 (2H, m), 2.70-3.30 (4H, m), 4.07 (2H, t, J=7.0 Hz), 4.60 (2H,s), 5.40-5.60 (1H, m), 6.60-6.80 (2H, m), 7.05 (1H, d, J=8.6 Hz),7.35-7.65 (3H, m), 7.75-8.10 (2H, m).

EXAMPLE 62-Hexyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0365] (1) The compound (1.20 g) obtained in Example 1(2) was dissolvedin N,N-dimethylformamide (12 ml). Thereto were added hexyl iodide (0.65ml) and potassium carbonate (0.82 g) and the mixture was stirred at 50°C. for 15 hr. Water (100 ml) was added to the reaction mixture, and themixture was extracted twice with ethyl acetate (50 ml). The ethylacetate layer was washed with saturated brine (100 ml) and dried overNa₂SO₄. Ethyl acetate was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive ethyl2-hexyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(1.05 g).

Ethyl2-hexyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

[0366] IR v (nujol) cm⁻¹; 1724, 1643, 1611.

[0367]¹H-NMR (CDCl₃) δ (ppm);

[0368] 0.88 (3H, br-t, J=5.0 Hz), 1.10-1.75 (11H, m), 2.35 (3H, s),2.50-2.80 (2H, m), 2.94 (2H, t, J=7.0 Hz), 3.02 (2H, d, J=5.5 Hz), 3.68(1H, t, J=5.5 Hz), 3.83 (1H, s), 3.94 (1H, s), 4.12 (2H, q, J=7.0 Hz),4.20 (2H, t, J=7.0 Hz), 6.50-6.80 (2H, m), 6.97 (1H, d, J=8.4 Hz),7.30-7.60 (3H, m), 7.80-8.10 (2H, m).

[0369] (2) The compound (1.0 g) obtained in (1) above was dissolved in10 ml of a mixed solution of tetrahydrofuran-methanol (3:1). Thereto wasadded 2N aqueous lithium hydroxide solution (5.1 ml), and the mixturewas stirred at room temperature for 11 hr. The solvent was evaporatedunder reduced pressure, and the obtained residue was acidified withcitric acid. The precipitated crystals were collected by filtration togive the title compound (0.80 g).

[0370] IR v (nujol) cm⁻¹; 1620, 1555, 1506.

[0371]¹H-NMR (CDCl₃) δ (ppm);

[0372] 0.89 (3H, br-t, J=6.0 Hz), 1.00-1.45 (6H, m), 1.50-1.90 (2H, m),2.36 (3H, s), 2.70-3.30 (2H, m), 2.93 (2H, t, J=6.2 Hz), 3.15 (2H, d,J=6.4 Hz), 3.75 (1H, t, J=6.4 Hz), 4.00-4.40 (4H, m), 6.23 (1H, br-s),6.60-6.85 (2H, m), 7.06 (1H, d, J=8.4 Hz), 7.30-7.60 (3H, m), 7.80-8.10(2H, m).

EXAMPLE 72-Isobutyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0373] (1) The compound (1.40 g) obtained in Example 1(2) was dissolvedin N,N-dimethylformamide (14 ml). Thereto were added isobutyl iodide(1.20 ml) and potassium carbonate (0.95 g), and the mixture was stirredat 50° C. for 3 days. Water (100 ml) was added to the reaction mixture,and the mixture was extracted twice with ethyl acetate (50 ml). Theobtained ethyl acetate layer was washed with saturated brine (100 ml)and dried over Na₂SO₄. Ethyl acetate was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give ethyl2-isobutyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(1.15 g).

Ethyl2-isobutyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

[0374] IR v (nujol) cm⁻¹; 1719, 1645, 1614, 1506.

[0375]¹H-NMR (CDCl₃) δ (ppm);

[0376] 0.89 (6H, d, J=6.6 Hz), 1.19 (3H, t, J=7.0 Hz), 1.70-1.90 (1H,m), 2.35 (3H, s), 2.10-2.50 (2H, m), 2.94 (2H, t, J=7.0 Hz), 3.02 (2H,d, J=5.2 Hz), 3.66 (1H, t, J=5.2 Hz), 3.83 (1H, s), 3.92 (1H, s), 4.16(2H, q, J=7.0 Hz), 4.20 (2H, t, J=7.0 Hz), 6.45-6.75 (2H, m), 6.97 (1H,d, J=8.2 Hz), 7.25-7.50 (3H, m), 7.85-8.10 (2H, m).

[0377] (2) The compound (1.05 g) obtained in (1) above was dissolved in10 ml of a mixed solution of tetrahydrofuran-methanol (3:1). Thereto wasadded 2N aqueous lithium hydroxide solution (5.7 ml), and the mixturewas stirred at room temperature for 24 hr. The solvent was evaporatedunder reduced pressure, and the obtained residue was acidified withcitric acid. The precipitated crystals were collected by filtration togive the title compound (0.83 g).

[0378] IR v (nujol) cm⁻¹; 3339, 1620, 1553, 1508.

[0379]¹H-NMR (CDCl₃) δ (ppm); 0.95 (3H, d, J=6.7 Hz), 1.01 (3H, d, J=7.0Hz), 1.95-2.15 (1H, m), 2.36 (3H, s), 2.60-2.80 (2H, m), 2.94 (2H, t,J=6.7 Hz), 3.16 (2H, d, J=6.6 Hz), 3.70 (1H, t, J=6.6 Hz), 4.11 (2H, s),4.18 (2H, t, J=6.6 Hz), 4.84 (1H, br-s), 6.60-6.90 (2H, m), 7.49 (1H, d,J=8.1 Hz), 7.25-7.50 (3H, m), 7.85-8.10 (2H, m).

EXAMPLE 82-Cyclohexylmethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0380] (1) The compound (1.40 g) obtained in Example 1(2) was dissolvedin N,N-dimethylformamide (14 ml). Thereto were added cyclohexylmethylbromide (1.44 ml) and potassium carbonate (0.95 g), and the mixture wasstirred at 50° C. for 2 days. Water (100 ml) was added to the reactionmixture, and the mixture was extracted twice with ethyl acetate (50 ml).The ethyl acetate layer was washed with saturated brine (100 ml) anddried over Na₂SO₄. Ethyl acetate was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive ethyl2-cyclohexylmethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(1.0 g).

Ethyl2-cyclohexylmethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

[0381] IR v (nujol) cm⁻¹; 1728, 1638, 1614, 1504.

[0382]¹H-NMR (CDCl₃) δ (ppm);

[0383] 0.80-2.00 (11H, m), 1.19 (3H, t, J=7.0 Hz), 2.36 (3H, s),2.40-2.55 (2H, m), 2.94 (2H, t, J=7.1 Hz), 3.00 (2H, d, J=5.3 Hz), 3.65(1H, t, J=5.3 Hz), 3.82 (1H, s), 3.92 (1H, s), 4.05 (2H, t, J=7.0 Hz),4.16 (2H, q, J=7.0 Hz), 6.50-6.80 (2H, m), 6.97 (1H, d, J=8.1 Hz),7.30-7.50 (3H, m), 7.80-8.10 (2H, m).

[0384] (2) The compound (0.95 g) obtained in (1) above was dissolved in28 ml of a mixed solution of tetrahydrofuran-methanol (3:1). Thereto wasadded 2N aqueous lithium hydroxide solution (7.13 ml), and the mixturewas stirred at room temperature for 3 days. The solvent was evaporatedunder reduced pressure, and the obtained residue was acidified withcitric acid. The precipitated crystals were collected by filtration togive the title compound (0.76 g).

[0385] IR v (nujol) cm⁻¹; 3319, 1624, 1506.

[0386]¹H-NMR (CDCl₃) δ (ppm);

[0387] 0.70-2.10 (11H, m), 2.36 (3H, s), 2.40-2.55 (2H, m), 2.93 (2H, t,J=6.4 Hz), 3.16 (2H, d, J=7.2 Hz), 3.70 (1H, t, J=7.2 Hz), 4.00-4.30(4H, m), 5.30 (1H, br-s), 6.60-6.90 (2H, m), 7.08 (1H, d, J=8.4 Hz),7.30-7.50 (3H, m), 7.80-8.10 (2H, m).

EXAMPLE 97-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-(3-phenylpropyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0388] (1) The compound (1.40 g) obtained in Example 1(2) was dissolvedin N,N-dimethylformamide (14 ml). Thereto were added 3-phenylpropylbromide (0.78 ml) and potassium carbonate (0.95 g), and the mixture wasstirred at 50° C. for 22 hr. Water (100 ml) was added to the reactionmixture, and the mixture was extracted twice with ethyl acetate (50 ml).The ethyl acetate layer was washed with saturated brine (100 ml) anddried over Na₂SO₄. Ethyl acetate was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive ethyl7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(3-phenylpropyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(1.05 g).

Ethyl7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(3-phenylpropyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0389] IR v (nujol) cm⁻¹; 1720, 1647, 1612, 1504.

[0390]¹H-NMR (CDCl₃) δ (ppm);

[0391] 1.17 (3H, t, J=7.0 Hz), 1.60-2.05 (2H, m), 2.35 (3H, s),2.50-2.80 (4H, m), 2.94 (2H, t, J=7.1 Hz), 3.04 (2H, d, J=5.7 Hz), 3.67(1H, t, J=5.7 Hz), 3.84 (1H, s), 3.94 (1H, s), 4.04 (2H, t, J=7.1 Hz),4.16 (2H, q, J=7.0 Hz), 6.50-6.80 (2H, m), 7.07 (1H, d, J=9.0 Hz), 7.20(5H, s), 7.10-7.50 (3H, m), 7.80-8.10 (2H, m).

[0392] (2) The compound (1.0 g) obtained in (1) above was dissolved in10 ml of a mixed solution of tetrahydrofuran-methanol (3:1). Thereto wasadded 2N aqueous lithium hydroxide solution (4.77 ml), and the mixturewas stirred at room temperature for 10 hr. The solvent was evaporatedunder reduced pressure, and the obtained residue was acidified withcitric acid. The precipitated crystals were collected by filtration togive the title compound (0.66 g).

[0393] IR v (nujol) cm⁻¹; 3346, 1616, 1556, 1506.

[0394]¹H-NMR (CDCl₃) δ (ppm);

[0395] 1.70-2.20 (3H, m), 2.35 (3H, s), 2.40-2.70 (4H, m), 2.70-3.30(2H, m), 2.92 (2H, t, J=6.3 Hz), 3.10 (2H, d, J=7.0 Hz), 3.65 (1H, t,J=7.0 Hz), 3.90-4.30 (4H, m), 5.12 (1H, br-s), 6.55-6.80 (2H, m),6.90-7.25 (6H, m), 7.25-7.55 (3H, m), 7.80-8.10 (2H, m).

EXAMPLE 102-Benzoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0396] (1) The compound (1.4 g) obtained in Example 1(2) was dissolvedin methylene chloride (14 ml). Thereto were added benzoyl chloride (0.48ml) and triethylamine (0.72 ml) under ice-cooling, and the mixture wasstirred at the same temperature for 15 min. Ethyl acetate (100 ml) wasadded to the reaction mixture, and the mixture was washed successivelywith 10% aqueous citric acid solution (50 ml), saturated aqueous sodiumhydrogencarbonate solution (50 ml) and then saturated brine (50 ml) anddried over Na₂SO₄. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive ethyl2-benzoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(1.16 g).

Ethyl2-benzoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0397] IR v (nujol) cm⁻¹; 1734, 1638, 1612, 1591.

[0398]¹H-NMR (CDCl₃) δ (ppm);

[0399] 0.75-1.15 (3H, m), 2.35 (3H, s), 2.93 (2H, t, J=6.6 Hz),3.05-3.25 (2H, m), 3.85-4.40 (4H, m), 4.20-4.80 (2H, m), 5.00-5.60 (1H,m), 6.47 (1H, br-s), 6.72 (1H, br-d, J=8.4 Hz), 7.05 (1H, br-d, J=8.4Hz), 7.30-7.60 (8H, m), 7.80-8.10 (2H, m).

[0400] (2) The compound (1.0 g) obtained in (1) above was dissolved in10 ml of a mixed solution of tetrahydrofuran-methanol (3:1). Thereto wasadded 1N aqueous lithium hydroxide solution (6.0 ml), and the mixturewas stirred at room temperature for 1.5 hr. The solvent was evaporatedunder reduced pressure. Thereto was added water (20 ml), and the mixturewas washed with ethyl acetate (10 ml). The obtained aqueous layer wasacidified with 6N hydrochloric acid, and the mixture was extracted twicewith diethyl ether (20 ml). The diethyl ether layer was washed withsaturated brine (30 ml) and dried over Na₂SO₄. Diethyl ether wasevaporated under reduced pressure. The obtained residue wasrecrystallized from methanol to give the title compound (0.75 g).

[0401] IR v (nujol) cm⁻¹; 1730, 1636, 1551.

[0402]¹H-NMR (CDCl₃) δ (ppm);

[0403] 2.32 (3H, s), 2.87 (2H, t, J=6.4 Hz), 3.00-3.35 (2H, m), 4.02(2H, t, J=6.4 Hz), 4.40-4.90 (2H, m), 4.90-5.30 (1H, br), 5.00-5.65 (1H,m), 6.40 (1H, br-s), 6.50-6.80 (1H, m), 7.03 (1H, d, J=8.4 Hz),7.20-7.60 (8H, m), 7.75-8.05 (2H, m).

EXAMPLE 11 Sodium2-benzyl-7-[2-(N-methyl-N-(pyridin-2-yl)amino)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0404] (1) Ethyl2-benzyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1.38g) was dissolved in N,N-dimethylformamide (10 ml). Thereto was addedsodium hydride (210 mg, 60% suspension in oil) under ice-cooling and themixture was stirred at room temperature for 30 min. Thereto was added2-(N-tert-butoxycarbonyl-N-methylamino)ethyl methanesulfonate (1.30 g)and the mixture was stirred further at the same temperature for 1 hr.Ethyl acetate (50 ml) was added to the reaction mixture, and the mixturewas washed with water (50 ml) and saturated brine (30 ml) and dried overNa₂SO₄. Ethyl acetate was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive ethyl2-benzyl-7-[2-(N-tert-butoxycarbonyl-N-methylamino)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(1.44 g).

Ethyl2-benzyl-7-[2-(N-tert-butoxycarbonyl-N-methylamino)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0405] IR v(neat) cm⁻¹; 2978, 2932, 1732, 1695, 1614.

[0406]¹H-NMR (CDCl₃) δ (ppm);

[0407] 1.23 (3H, t, J=7.0 Hz), 1.44 (9H, s), 2.95 (3H, s), 3.08 (2H, d,J=4.9 Hz), 3.54 (2H, t, J=5.5 Hz), 3.60-4.30 (7H, m), 6.50 (1H, d, J=2.0Hz), 6.68 (1H, dd, J=2.0, 8.1 Hz), 7.01 (1H, d, J=8.1 Hz), 7.20-7.50(5H, m).

[0408] (2) The compound (1.44 g) obtained in (1) above was dissolved informic acid (7.0 ml). Thereto was added 8.78N hydrogen chloride solution(2.0 ml) in 2-propanol, and the mixture was stirred at room temperaturefor 15 min. Ethyl acetate (100 ml) was added to the reaction mixture,and the mixture was neutralized with saturated aqueous sodiumhydrogencarbonate solution, and then the two layers were separated. Theobtained ethyl acetate layer was washed with saturated brine (50 ml) anddried over Na₂SO₄. Ethyl acetate was evaporated under reduced pressureto give ethyl2-benzyl-7-(2-methylaminoethoxy)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(1.08 g).

Ethyl2-benzyl-7-(2-methylaminoethoxy)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0409] IR v (neat) cm⁻¹; 3332, 1732, 1612, 1504.

[0410]¹H-NMR (CDCl₃) δ (ppm);

[0411] 1.22 (3H, t, J=7.0 Hz), 2.41 (1H, br-s), 2.49 (3H, s), 2.95 (2H,t, J=5.5 Hz), 3.08 (2H, d, J=4.9 Hz), 3.60-4.25 (7H, m), 6.52 (1H, d,J=2.0 Hz), 6.70 (1H, dd, J=2.0, 8.4 Hz), 7.00 (1H, d, J=8.4 Hz),7.20-7.50 (5H, m).

[0412] (3) The compound (1.05 g) obtained in (2) above was dissolved in2-chloropyridine (2.0 ml), and the mixture was stirred at 140° C. for 16hr. The reaction mixture was purified by silica gel columnchromatography to give ethyl2-benzyl-7-[2-(N-methyl-N-(pyridin-2-yl)amino)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(0.5 g).

Ethyl2-benzyl-7-[2-(N-methyl-N-(pyridin-2-yl)amino)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0413] IR v (neat) cm⁻¹; 2932, 2905, 1732, 1597, 1560, 1504.

[0414]¹H-NMR (CDCl₃) δ (ppm);

[0415] 1.22 (3H, t, J=7.0 Hz), 3.06 (2H, d, J=6.2 Hz), 3.11 (3H, s),3.60-4.30 (11H, m), 6.40-6.80 (4H, m), 6.97 (1H, d, J=8.4 Hz), 7.20-7.50(6H, m), 8.00-8.20 (1H, m).

[0416] (4) The compound (488 mg) obtained in (3) above was dissolved in5.0 ml of a mixed solution of tetrahydrofuran-methanol (3:1). Theretowas added 1N aqueous sodium hydroxide solution (2.2 ml), and the mixturewas stirred at room temperature for 6 hr. The solvent was evaporatedunder reduced pressure. Water (10 ml) and then saline were added tosupersaturation, and the mixture was extracted three times with ethylacetate (30 ml). The ethyl acetate layer was washed with saturated brine(10 ml) and dried over Na₂SO₄. Ethyl acetate was evaporated underreduced pressure. Diethyl ether was added to the obtained residue. Thesolid was collected by filtration to give the title compound (356 mg).

[0417] IR v (nujol) cm⁻¹; 1597, 1497.

[0418]¹H-NMR (MeOH-d₄) δ (ppm);

[0419] 2.95-3.20 (2H, m), 3.07 (3H, s), 3.40-4.20 (9H, m), 6.40-6.70(4H, m), 6.92 (1H, d, J=8.4 Hz), 7.20-7.50 (3H, m), 7.90-8.15 (1H, m).

EXAMPLE 12 Sodium2-benzyl-7-[2-(5-ethyl-pyridin-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0420] (1) Ethyl2-benzyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1.0g) was dissolved in N,N-dimethylformamide (10 ml). Thereto was addedsodium hydride (200 mg, 60% suspension in oil) under ice-cooling and themixture was stirred at room temperature for 30 min to give solution (A).Separately, 5-ethyl-2-pyridineethanol (1.5 g) and triethylamine (1.68ml) were dissolved in methylene chloride (40 ml). Thereto was addedtrifluoromethanesulfonic anhydride (2.0 ml) under ice-cooling, and themixture was stirred at room temperature for 30 min. The reaction mixturewas washed with water (30 ml) and dried over Na₂SO₄. Methylene chloridewas evaporated under reduced pressure. The obtained5-ethyl-2-pyridineethyl trifluoromethanesulfonate (2.81 g) was added tothe above-mentioned solution (A), and the mixture was stirred at roomtemperature for 30 min. Ethyl acetate (100 ml) was added to the reactionmixture, and the mixture was washed with water (50 ml) and saturatedbrine (50 ml) and dried over Na₂SO₄. Ethyl acetate was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give ethyl 2-benzyl-7-[2-(5-ethyl-pyridin-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(0.58 g).

Ethyl2-benzyl-7-[2-(5-ethyl-pyridin-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0421] IR v (nujol) cm⁻¹; 1732, 1612, 1504.

[0422]¹H-NMR (CDCl₃) δ (ppm);

[0423] 1.22 (6H, t, J=7.2 Hz), 2.61 (2H, q, J=7.2 Hz), 3.07 (2H, d,J=5.5 Hz), 3.18 (2H, t, J=6.6 Hz), 3.72 (1H, t, J=5.5 Hz), 3.81 (1H, s),3.90 (4H, s), 4.13 (2H, q, J=7.2 Hz), 4.27 (2H, t, J=6.6 Hz), 6.51 (1H,d, J=2.0 Hz), 6.69 (1H, dd, J=2.0, 8.4 Hz), 6.98 (1H, d, J=8.4 Hz),7.10-7.50 (7H, m), 8.00-8.20 (1H, m).

[0424] (2) The compound (0.94 g) obtained in (1) above was dissolved in40 ml of a mixed solution of tetrahydrofuran-methanol (3:1). Thereto wasadded 2N aqueous sodium hydroxide solution (6.0 ml), and the mixture wasstirred at 40° C. for 2 hr. The solvent was evaporated under reducedpressure. Water (10 ml) and then sodium chloride were added tosupersaturation, and the mixture was extracted three times with ethylacetate (30 ml). The ethyl acetate layer was washed with saturated brine(10 ml) and dried over Na₂SO₄. Ethyl acetate was evaporated underreduced pressure. Diisopropyl ether was added to the obtained residue.The solid was collected by filtration to give the title compound (0.58g).

[0425] IR v (nujol) cm⁻¹; 1576, 1504.

[0426]¹H-NMR (MeOH-d₄) δ (ppm);

[0427] 1.22 (6H, t, J=7.5 Hz), 2.63 (2H, q, J=7.5 Hz), 2.90-3.20 (4H,m), 3.72 (1H, s), 3.85 (1H, s), 3.95-4.35 (5H, m), 4.27 (2H, t, J=6.6Hz), 6.40-6.75 (2H, m), 6.91 (1H, d, J=8.4 Hz), 7.20-7.65 (7H, m),8.20-8.35 (1H, m).

EXAMPLE 132-Benzyl-7-[2-(indolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0428] (1) Ethyl2-benzyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1.0g) was dissolved in N,N-dimethylformamide (10 ml). Thereto was addedsodium hydride (154 mg, 60% suspension in oil) under ice-cooling and themixture was stirred at the same temperature for 30 min.1-(2-Bromoethyl)indoline (1.09 g) was added and the mixture was furtherstirred at room temperature for 2 hr. Ethyl acetate (100 ml) was addedto the reaction mixture, and the mixture was washed with water (100 ml)and saturated brine (50 ml) and dried over Na₂SO₄. Ethyl acetate wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography to give ethyl2-benzyl-7-[2-(indolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(1.18 g).

Ethyl2-benzyl-7-[2-(indolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0429] IR v(neat) cm⁻¹; 2926, 2843, 1732, 1609, 1493.

[0430]¹H-NMR (CDCl₃) δ (ppm);

[0431] 1.22 (3H, t, J=7.2 Hz), 2.95 (2H, t, J=8.3 Hz), 3.08 (2H, d,J=5.3 Hz), 3.20-3.60 (3H, m), 3.60-4.30 (10H, m), 6.40-6.80 (4H, m),6.80-7.20 (3H, m), 7.20-7.50 (5H, m).

[0432] (2) The compound (1.17 g) obtained in (1) above was dissolved in24 ml of a mixed solution of tetrahydrofuran-methanol (3:1). Thereto wasadded IN aqueous lithium hydroxide solution (7.69 ml), and the mixturewas stirred at 50° C. for 1 hr. The solvent was evaporated under reducedpressure, and the obtained residue was acidified with citric acid. Theprecipitated crystals were collected by filtration to give the titlecompound (0.93 g).

[0433] IR v (nujol) cm⁻¹; 1634, 1609, 1491.

[0434]¹H-NMR (CDCl₃) δ (ppm);

[0435] 2.95 (2H, br-t, J=8.2 Hz), 3.16 (2H, br-d, J=6.1 Hz), 3.25-3.60(3H, m), 3.60-4.40 (8H, m), 4.07 (2H, s), 4.10 (2H, t, J=5.5 Hz), 4.13(2H, q, J=7.2 Hz), 5.60-6.30 (1H, br), 6.30-6.85 (4H, m), 6.85-7.20 (3H,m), 7.32 (5H, s).

EXAMPLE 14 Ethyl2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0436] Ethyl2-benzyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (10.0g) and 2-(5-methyl-2-phenyloxazol-4-yl)ethyl methanesulfonate (18.01 g)were dissolved in N,N-dimethylformamide (200 ml). Thereto was addedpotassium carbonate (13.3 g) and the mixture was stirred at 80° C. for10 hr. Water (1 L) was added to the reaction mixture, and the mixturewas extracted twice with ethyl acetate (200 ml). The ethyl acetate layerwas washed with saturated brine (500 ml) and dried over Na₂SO₄. Ethylacetate was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography to give the title compound(7.06 g).

[0437] IR and NMR spectrum corresponded to those obtained in Example2(1).

EXAMPLE 15 Methyl7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0438] (1) Methyl2-tert-butoxycarbonyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(15.16 g) and 2-(5-methyl-2-phenyloxazol-4-yl)ethyl methanesulfonate(20.0 g) were dissolved in N,N-dimethylformamide (300 ml). Thereto wasadded potassium carbonate (19.7 g) and the mixture was stirred at 80° C.for 3.5 hr. Water (1 L) was added to the reaction mixture, and themixture was extracted twice with ethyl acetate (300 ml). The ethylacetate layer was washed with saturated brine (500 ml) and dried overNa₂SO₄. Ethyl acetate was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive methyl2-tert-butoxycarbonyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(14.0 g).

Methyl2-tert-butoxycarbonyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0439]¹H-NMR (CDCl₃) δ (ppm);

[0440] 1.46, 1.50 (9H, s, s), 2.36 (3H, s), 2.95 (2H, t, J=6.8 Hz),2.90-3.30 (2H, m), 3.60 (3H, s), 4.21 (2H, t, J=6.8 Hz), 4.50, 4.60 (2H,s, s), 4.70-4.90, 5.00-5.20 (1H, m, m), 6.60-6.90 (2H, m), 7.12 (1H, d,J=8.4 Hz), 7.30-7.55 (3H, m), 7.90-8.15 (2H, m).

[0441] (2) The compound (14.0 g) obtained in (1) above was dissolved informic acid (42 ml). Thereto was added 8.78N hydrogen chloride solution(10.7 ml) in 2-propanol under ice-cooling, and the mixture was stirredat room temperature for 20 min. Ethyl acetate (300 ml) and water (500ml) were added to the reaction mixture, and the mixture was neutralizedwith sodium hydrogencarbonate and the two layers were separated. Theobtained ethyl acetate layer was washed with saturated brine (500 ml)and dried over Na₂SO₄. Ethyl acetate was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound (9.4 g).

[0442] IR v (nujol) cm⁻¹; 3560, 1744, 1643, 1612, 1578, 1553, 1504.

[0443]¹H-NMR (CDCl₃) δ (ppm);

[0444] 1.92 (1H, s), 2.36 (3H, s), 2.80-3.20 (4H, m), 3.60-3.85 (1H, m),3.76 (3H, s), 4.04 (2H, s), 4.21 (2H, t, J=6.6 Hz,), 6.57 (1H, d, J=2.0Hz), 6.71 (1H, dd, J=2.0, 8.6 Hz), 7.00 (1H, d, J=8.6 Hz), 7.30-7.60(3H, m), 7.85-8.15 (2H, m).

EXAMPLE 162-(4-Methoxybenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0445] (1) The compound (800 mg) of Example 15 was dissolved inN,N-dimethylformamide (8 ml). Thereto was added sodium hydride (96 mg,60% suspension in oil) under ice-cooling and the mixture was stirred atroom temperature for 30 min. To the obtained mixture was dropwise added4-methoxybenzyl chloride (0.41 ml), and the mixture was stirred furtherat 50° C. for 3 hr. Ethyl acetate (50 ml) was added to the reactionmixture, and the mixture was washed water (50 ml) and saturated brine(30 ml) and dried over Na₂SO₄. Ethyl acetate was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography to give methyl2-(4-methoxybenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(0.82 g). Methyl2-(4-methoxybenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

[0446] IR v (nujol) cm⁻¹; 1736, 1638, 1614, 1553, 1514

[0447]¹H-NMR (CDCl₃) δ (ppm);

[0448] 2.35 (3H, s), 2.93 (2H, t, J=6.6 Hz), 3.05 (2H, d, J=5.5 Hz),3.66 (3H, s), 3.70-4.00 (8H, m), 4.17 (2H, t, J=6.6 Hz), 6,50 (1H, d,J=2.0 Hz), 6.68 (1H, dd, J=2.0, 8.6 Hz), 6.85 (2H, d, J=8.6 Hz), 6.98(1H, d, J=8.6 Hz), 7.28 (2H, d, J=8.6 Hz), 7.30-7.50 (3H, m), 7.80-8.10(2H, m).

[0449] (2) The compound (450 mg) obtained in (1) above was dissolved in10 ml of a mixed solution of tetrahydrofuran-methanol (3:1). Thereto wasadded 2N aqueous lithium hydroxide solution (2.5 ml), and the mixturewas stirred at room temperature for 3 hr. The solvent was evaporatedunder reduced pressure, and the obtained residue was acidified withcitric acid. The precipitated crystals were collected by filtration togive the title compound (350 mg).

[0450] IR v (nujol) cm⁻¹; 3288, 1612, 1555, 1514.

[0451]¹H-NMR (CDCl₃) δ (ppm);

[0452] 2.35 (3H, s), 2.93 (2H, t, J=6.4 Hz), 3.18 (2H, d, J=6.8 Hz),3.70-4.10 (5H, m), 3.77 (3H, s), 4.17 (2H, t, J=6.4 Hz), 4.50 (1H,br-s), 6.60 (1H, d, J=2.0 Hz), 6.65-6.95 (3H, m), 7.08 (2H, d, J=8.4Hz), 7.20-7.60 (5H, m), 7.80-8.10 (2H, m).

EXAMPLE 17 Ethyl2-(4-methoxybenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0453] In the same manner as in Example 16(1), the title compound wasobtained.

[0454]¹H-NMR (CDCl₃) δ (ppm);

[0455] 1.21 (3H, t, J=7.0 Hz), 2.34 (3H, s), 2.91 (2H, t, J=7.0 Hz),3.04 (2H, d, J=5.5 Hz), 3.60-3.95 (8H, m), 4.12 (2H, q, J=7.0 Hz), 4.15(2H, t, J=7.0 Hz), 6.51 (1H, d, J=2.0 Hz), 6.67 (1H, dd, J=2.0, 8.8 Hz),6.75-7.00 (3H, m), 7.15-7.50 (5H, m), 7.85-8.10 (2H, m).

EXAMPLE 182-(4-Methylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0456] (1) The compound (800 mg) of Example 15 was dissolved inN,N-dimethylformamide (8.0 ml). Thereto was added sodium hydride (96 mg,60% suspension in oil) under ice-cooling and the mixture was stirred atroom temperature for 30 min. To the obtained mixture was dropwise addedα-chloro-p-xylene (0.40 ml), and the mixture was stirred at 50° C. for 3hr and further stirred at room temperature for 15 hr. Ethyl acetate (50ml) was added to the reaction mixture, and the mixture was washed withwater (50 ml) and saturated brine (30 ml) and dried over Na₂SO₄. Ethylacetate was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography to give methyl2-(4-methylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(0.90 g).

Methyl2-(4-methylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0457] IR v (nujol) cm⁻¹; 1736, 1639, 1614, 1595, 1551.

[0458]¹H-NMR (CDCl₃) δ (ppm);

[0459] 2.34 (6H, s), 2.93 (2H, t, J=6.7 Hz), 3.06 (2H, d, J=5.0 Hz),3.50-4.00 (5H, m), 3.65 (3H, s), 4.17 (2H, t, J=6.7 Hz), 6.51 (1H, d,J=2.0 Hz), 6.68 (1H, dd, J=2.0, 8.6 Hz), 6.98 (2H, d, J=8.6 Hz), 7.11(2H, d, J=8.4 Hz), 7.26 (2H, d, J=8.4 Hz), 7.30-7.55 (3H, m), 7.80-8.15(2H, m).

[0460] (2) The compound (608 mg) obtained in (1) above was dissolved in17 ml of a mixed solution of tetrahydrofuran-methanol (3:1). Thereto wasadded 1N aqueous lithium hydroxide solution (6.1 ml), and the mixturewas stirred at room temperature for 3 hr. The solvent was evaporatedunder reduced pressure, and the obtained residue was acidified withcitric acid. The precipitated crystals were collected by filtration togive the title compound (400 mg).

[0461] IR v (nujol) cm⁻¹; 1620, 1555, 1506.

[0462]¹H-NMR (CDCl₃) δ (ppm);

[0463] 2.32 (3H, s), 2.35 (3H, s), 2.93 (2H, t, J=7.0 Hz), 3.17 (2H, d,J=6.6 Hz), 3.65-4.05 (5H, m), 4.17 (2H, t, J=7.0 Hz), 4.73 (1H, br-s),6.60 (1H, d, J=2.0 Hz), 6.77 (1H, dd, J=2.0, 8.8 Hz), 6.95-7.60 (8H, m),7.85-8.10 (2H, m).

EXAMPLE 19 Ethyl2-(4-methylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0464] In the same manner as in Example 18(1), the title compound wasobtained.

[0465]¹H-NMR (CDCl₃) δ (ppm);

[0466] 1.21 (3H, t, J=7.0 Hz), 2.34 (3H, s), 2.92 (2H, t, J=7.0 Hz),3.05 (2H, d, J=5.4 Hz), 3.71 (1H, t, J=5.4 Hz), 3.80 (1H, s), 3.92 (1H,s), 4.12 (2H, q, J=7.0 Hz), 4.16 (2H, t, J=7.0 Hz), 6.51 (1H, d, J=2.0Hz), 6.68 (1H, dd, J=2.0, 8.4 Hz), 6.98 (1H, d, J=8.4 Hz), 7.00-7.60(7H, m), 7.80-8.10 (2H, m).

EXAMPLE 202-Benzyl-7-[2-(6-carboxyindolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0467] (1) Ethyl2-benzyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1.0g) was dissolved in N,N-dimethylformamide (10 ml). Thereto was addedsodium hydride (154 mg, 60% suspension in oil) under ice-cooling and themixture was stirred at the same temperature for 30 min. To the obtainedmixture was added 1-(2-bromoethyl)-6-methoxycarbonylindoline (1.36 g),and the mixture was stirred further at room temperature for 4 hr. Ethylacetate (100 ml) was added to the reaction mixture, and the mixture waswashed water (100 ml) and saturated brine (50 ml) and dried over Na₂SO₄.Ethyl acetate was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography to give ethyl2-benzyl-7-[2-(6-methoxycarbonylindolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(1.18 g).

Ethyl2-benzyl-7-[2-(6-methoxycarbonylindolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0468] IR v(neat) cm⁻¹; 2949, 2841, 1717, 1611, 1587, 1497.

[0469]¹H-NMR (CDCl₃) δ (ppm);

[0470] 1.23 (3H, t, J=7.2 Hz), 2.99 (2H, t, J=8.8 Hz), 3.00-3.25 (2H,m), 3.35-4.35 (13H, m), 3.87 (3H, s), 6.52 (1H, d, J=2.4 Hz), 6.70 (1H,dd, J=2.4, 8.3 Hz), 6.90-7.20 (3H, m), 7.20-7.55 (6H, m).

[0471] (2) The compound (1.31 g) obtained in (1) above was dissolved in33 ml of a mixed solution of tetrahydrofuran-methanol (3:1). Thereto wasadded 1N aqueous lithium hydroxide solution (15.3 ml), and the mixturewas stirred at 50° C. for 2 hr. The solvent was evaporated under reducedpressure, and the obtained residue was acidified with citric acid. Theprecipitated crystals were collected by filtration to give the titlecompound (1.0 g).

[0472] IR v (nujol) cm⁻¹; 3400, 1693, 1612, 1497.

[0473]¹H-NMR (MeOH-d₄) δ (ppm);

[0474] 2.96 (2H, br-t, J=8.0 Hz), 3.15-3.75 (3H, m), 3.80-4.50 (10H, m),6.65-7.70 (11H, m).

EXAMPLE 212-(4-Fluorobenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0475] (1) The compound (1.00 g) obtained in Example 15 was dissolved inN,N-dimethylformamide (20 ml). Thereto were added 4-fluorobenzylchloride (0.46 ml), potassium carbonate (0.53 g) and potassium iodide(0.21 g), and the mixture was stirred at 50° C. for 1.5 hr. Ethylacetate (50 ml) was added to the reaction mixture, and the mixture waswashed with water (100 ml) and saturated brine (100 ml) and dried overNa₂SO₄. Ethyl acetate was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography togive methyl2-(4-fluorobenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(0.92 g).

Methyl2-(4-fluorobenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0476] IR v (nujol) cm⁻¹; 1738, 1639, 1616, 1551, 1510

[0477]¹H-NMR (CDCl₃) δ (ppm);

[0478] 2.35 (3H, s), 2.93 (2H, t, J=6.8 Hz), 3.07 (2H, d, J=5.0 Hz),3.55-4.00 (5H, m), 3.65 (3H, s), 4.18 (2H, t, J=6.8 Hz), 6.51 (1H, d,J=2.0 Hz), 6.70 (1H, dd, J=2.0, 8.6 Hz), 6.80-7.15 (3H, m), 7.15-7.50(5H, m), 7.80-8.15 (2H, m).

[0479] (2) The compound (900 mg) of (1) above was dissolved in 18 ml ofa mixed solution of tetrahydrofuran-methanol (3:1). Thereto was added 1Naqueous lithium hydroxide solution (8.9 ml), and the mixture was stirredat room temperature for 3 hr. The solvent was evaporated under reducedpressure, and the obtained residue was acidified with citric acid. Theprecipitated crystals were collected by filtration to give the titlecompound (0.68 g).

[0480] IR v (nujol) cm⁻¹; 3398, 1614, 1555, 1510.

[0481]¹H-NMR (CDCl₃) δ (ppm);

[0482] 2.36 (3H, s), 2.94 (2H, t, J=6.4 Hz), 3.15 (2H, d, J=6.4 Hz),3.45-4.00 (5H, m), 4.19 (2H, t, J=6.4 Hz), 6.60 (1H, d, J=2.0 Hz), 6.75(1H, dd, J=2.0, 8.6 Hz), 6.90-7.55 (8H, m), 7.90-8.10 (2H, m).

EXAMPLE 222-(2,2-Dimethylpropionyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0483] Methyl7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(0.60 g) was dissolved in methylene chloride (6 ml). Thereto were addedpivaloyl chloride (0.22 ml) and triethylamine (0.32 ml) underice-cooling, and the mixture was stirred at the same temperature for 15min. Ethyl acetate (100 ml) was added to the reaction mixture, and themixture was washed successively with 10% aqueous citric acid solution(50 ml), saturated aqueous sodium hydrogencarbonate solution (50 ml) andsaturated brine (50 ml) and dried over Na₂SO₄. The solvent wasevaporated under reduced pressure. The obtained residue was dissolved in18 ml of a mixed solution of tetrahydrofuran -methanol (3:1). Theretowas added 1N aqueous lithium hydroxide solution (4.6 ml), and themixture was stirred at 50° C. for 30 min. The solvent was evaporatedunder reduced pressure. Thereto was added water (20 ml) and the mixturewas acidified with citric acid. The obtained mixture was extracted withethyl acetate (50 ml). The ethyl acetate layer was washed with saturatedbrine (30 ml) was dried over Na₂SO₄. Ethyl acetate was evaporated underreduced pressure to give the title compound (0.65 g).

[0484] IR v (nujol) cm⁻¹; 1734, 1630, 1612, 1553.

[0485]¹H-NMR (DMSO-d₆) δ (ppm);

[0486] 1.24 (9H, s), 2.36 (3H, s), 2.80-4.00 (1H, br), 2.92 (2H, t,J=6.4 Hz), 2.95-3.15 (2H, m), 4.18 (2H, t, J=6.4 Hz), 4.41, 4.91 (2H,ABq, J=18.1 Hz), 4.90-5.15 (1H, m), 6.77 (1H, dd, J=2.0, 8.1 Hz), 6.89(1H, d, J=2.0 Hz), 7.09 (1H, d, J=8.1 Hz), 7.30-7.65 (3H, m), 7.80-8.10(2H, m).

EXAMPLE 232-(2,2-Dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S.)-carboxylicacid

[0487] The title compound (1.66 g) of Example 22 was dissolved inpyridine (16.6 ml). Thereto was added sodium borohydride (1.36 g) andthe mixture was stirred at 100° C. for 4 hr. The mixture was acidifiedwith 10% aqueous citric acid solution and extracted with ethyl acetate(100 ml). The ethyl acetate layer was washed successively by adding 10%aqueous citric acid solution (100 ml) and saturated brine (50 ml) anddried over Na₂SO₄. Ethyl acetate was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography togive the title compound (0.84 g).

[0488] IR v (nujol) cm⁻¹; 3391, 3279, 1668, 1645, 1616, 1597, 1497.

[0489]¹H-NMR (CDCl₃) δ (ppm);

[0490] 0.96 (9H, s), 2.35 (3H, s), 2.46, 2.73 (2H, ABq, J=13.9 Hz), 2.93(2H, t, J=6.7 Hz), 3.03-3.23 (2H, m), 3.57-3.78 (1H, m), 3.91, 4.18 (1H,ABq, J=15.4 Hz), 4.17 (2H, t, J=6.7 Hz), 5.60-6.05 (1H, br), 6.60 (1H,d, J=2.0 Hz), 6.73 (1H, dd, J=2.0, 8.4 Hz), 7.04 (1H, d, J=8.4 Hz),7.30-7.55 (3H, m), 7.80-8.10 (2H, m).

EXAMPLE 242-(2,2-Dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0491] (1) Methyl2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0492] Methyl2-(2,2-dimethylpropyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(1.5 g) and 2-(5-methyl-2-phenyloxazol-4-yl)ethyl methanesulfonate (2.59g) were dissolved in toluene (45 ml). Thereto were added potassiumcarbonate (2.24 g) and tetraethylammomium fluoride (0.60 g) and themixture was stirred at 80° C. for 3 hr. The reaction mixture was washedsuccessively with water (50 ml) and saturated brine (50 ml) and driedover Na₂SO₄. Toluene was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography to give methyl2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(2.77 g).

[0493] 1H-NMR (CDCl₃) δ (ppm);

[0494] 0.88 (9H, s), 2.35, 2.58 (2H, ABq, J=14.5 Hz), 2.36 (3H, s), 2.46(2H, t, J=6.8 Hz), 2.95-3.20 (2H, m), 3.60 (3H, s), 3.60-3.80 (1H, m),3.85-4.20 (2H, m), 4.19 (2H, t, J=6.8 Hz), 6.54 (1H, d, J=2.0 Hz), 6.68(1H, dd, J=2.0, 8.4 Hz), 6.98 (1H, d, J=8.4 Hz), 7.30-7.50 (3H, m),7.85-8.05 (2H, m).

[0495] (2) The compound (5.0 g) of (1) above was dissolved in 130 ml ofa mixed solution of tetrahydrofuran-methanol (3:1). Thereto was added iNaqueous lithium hydroxide solution (54 ml), and the mixture was stirredat 50° C. for 3.5 hr and acidified with 6N hydrochloric acid. Thesolvent was evaporated under reduced pressure. The obtained residue wasextracted with ethyl acetate (200 ml). The ethyl acetate layer waswashed with saturated brine (100 ml) and dried over Na₂SO₄. Ethylacetate was evaporated under reduced pressure. The obtained residue wasdissolved in ethanol (25 ml). Thereto was added water (150 ml) and themixture was stirred at room temperature to allow crystallization. Theprecipitated crystals were collected by filtration to give the titlecompound (4.52 g).

[0496] IR and ¹H-NMR NMR spectrum are correspondent to that obtained inExample 23.

EXAMPLE 252-Benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid hydrochloride

[0497] The title compound (675 mg) of Example 2 was dissolved in 75%ethanol (10.1 ml) under heating. Thereto was added 6N hydrochloric acid(2.23 ml), and the mixture was stood at room temperature for 2 hr toallow crystallization. The precipitated crystals were colleted byfiltration to give the title compound (625 mg).

[0498] IR v (nujol) cm⁻¹; 3398, 1734, 1680, 1641, 1620, 1587, 1574,1551.

[0499]¹H-NMR (DMSO-d₆) δ (ppm);

[0500] 2.36 (3H, s), 2.92 (2H, t, J=6.0 Hz), 3.00-3.70 (2H, m), 4.19(2H, t, J=6.0 Hz), 4.25-4.75 (5H, m), 4.80-6.70 (2H, br), 6.70-7.05 (2H,m), 7.20 (1H, d, J=8.6 Hz), 7.30-7.77 (8H, m), 7.80-8.10 (2H, m).

EXAMPLE 26 Sodium2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0501] The title compound (1.0 g) of Example 2 was suspended in methanol(10 ml). Thereto was added a 2.09N sodium hydroxide solution (1.02 ml)in methanol. After dissolution, methanol was evaporated under reducedpressure. Diethyl ether was added to the obtained residue, and theprecipitated crystals were collected by filtration to give the titlecompound (1.03 g)

[0502] IR v (nujol) cm⁻¹; 1638, 1589, 1503.

[0503]¹H-NMR (DMSO-d₆) δ (ppm);

[0504] 2.33 (3H, s), 2.55-3.60 (6H, m), 3.60-4.30 (5H, m), 6.47 (1H, s),6.60 (1H, d, J=8.6 Hz), 6.92 (1H, d, J=8.6 Hz), 7.00-7.67 (8H, m),7.67-8.05 (2H, m).

EXAMPLE 272-(2,2-Dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid hydrochloride

[0505] The title compound (2.1 g) of Example 23 was dissolved inmethanol (10.5 ml). 8.78N Hydrogen chloride solution (1.07 ml) inisopropanol and then ethyl acetate (50 ml) were added to the mixture andthe mixture was stirred at room temperature for crystallization. Theprecipitated crystals were collected by filtration to give the titlecompound (1.03 g).

[0506] IR v (nujol) cm⁻¹; 3362, 3206, 1740, 1672, 1612, 1576, 1553.

[0507]¹H-NMR (DMSO-d₆) δ (ppm);

[0508] 1.12 (9H, s), 2.37 (3H, s), 2.65-3.50 (6H, m), 4.21 (2H, t, J=6.5Hz), 4.40-4.80 (3H, m), 4.85-6.50 (2H, br), 6.90 (1H, d, J=8.1 Hz), 6.94(1H, s), 7.21 (1H, d, J=8.1 Hz), 7.35-7.65 (3H, m), 7.80-8.05 (2H, m).

EXAMPLE 282-(2,2-Dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid sulfate

[0509] The title compound (0.5 g) of Example 23 was dissolved inmethanol (1.25 ml). Sulfuric acid (0.3 ml) and then water (16.8 ml) wereadded to the mixture and the mixture was stirred at room temperature forcrystallization. The precipitated crystals were collected by filtrationto give the title compound (0.25 g).

[0510] IR v (nujol) cm⁻¹; 3400, 1715, 1650, 1615, 1550.

[0511]¹H-NMR (DMSO-d₆) δ (ppm);

[0512] 0.93 (9H, s), 2.36 (3H, s), 2.40-3.30 (6H, m), 3.75-4.45 (5H, m),4.60-6.50 (2H, br), 6.70 (1H, br-s), 6.74 (1H, d, J=8.1 Hz), 7.06 (1H,d, J=8.1 Hz), 7.25-7.65 (3H, m), 7.75-8.10 (2H, m).

EXAMPLE 292-(2,2-Dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid tosylate

[0513] The title compound (0.5 g) of Example 23 and p-toluenesulfonicacid (0.28 g) were dissolved in ethanol (10 ml) under heating. Aftercrystallization at room temperature under stirring, the precipitatedcrystals were collected by filtration to give the title compound (0.3g).

[0514] IR v (nujol) cm⁻¹; 3047, 1734, 1645, 1612, 1514.

[0515]¹H-NMR (DMSO-d₆) δ (ppm);

[0516] 1.07 (9H, s), 2.28 (3H, s), 2.36 (3H, s), 2.70-3.50 (6H, m), 4.21(2H, t, J=6.5 Hz), 4.40-4.80 (3H, m), 6.80-7.35 (5H, m), 7.35-7.65 (5H;m), 7.75-8.05 (2H, m), 8.40-12.00 (2H, br).

EXAMPLE 302-(2,2-Dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid fumarate

[0517] The title compound (1.0 g) of Example 23 and fumaric acid (0.23g) were dissolved in methanol (5 ml). Water (5 ml) was added to themixture and the mixture was stirred at room temperature forcrystallization. The precipitated crystals were collected by filtrationto give the title compound (0.94 g).

[0518] IR v (nujol) cm⁻¹; 3500, 3395, 1680, 1650, 1625, 1575, 1550.

[0519]¹H-NMR (DMSO-d₆) δ (ppm);

[0520] 0.85 (9H, s), 2.00-6.30 (2H, br), 2.35 (3H, s), 2.32, 2.59 (2H,ABq, J=14.9 Hz), 2.75-3.10 (2H, m), 2.85 (2H, t, J=6.6 Hz), 3.45-4.30(3H, m), 4.15 (2H, t, J=6.6 Hz), 6.61 (1H, d, J=2.2 Hz), 6.64 (1H, s),6.66 (1H, dd, J=2.2, 8.4 Hz), 7.00 (1H, d, J=8.4 Hz), 7.35-7.65 (3H, m),7.75-8.10 (2H, m).

EXAMPLE 31 Calcium2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0521] The title compound (0.9 g) of Example 23 was dissolved in ethanol(9 ml). 0.04N Aqueous calcium hydroxide solution (54 ml) was added tothe mixture and the mixture was stirred at room temperature forcrystallization. The precipitated crystals were collected by filtrationto give the title compound (0.79 g).

[0522] IR v (nujol) cm⁻¹; 3396, 1638, 1611, 1556, 1504.

[0523]¹H-NMR (MeOH-d₄) δ (ppm);

[0524] 0.87 (9H, s), 2.34 (3H, s), 2.36, 2.58 (2H, ABq, J=14.0 Hz),2.80-3.10 (2H, m), 2.90 (2H, t, J=6.5 Hz), 3.30-3.80 (3H, m), 4.15 (2H,t, J=6.5 Hz), 6.50 (1H, d, J=2.4 Hz), 6.60 (1H, dd, J=2.4, 8.2 Hz), 6.90(1H, d, J=8.2 Hz), 7.30-7.60 (3H, m), 7.80-8.05 (2H, m).

[0525] The following compounds were synthesized in the same manner as inExamples 1-24.

EXAMPLE 322-Benzyl-7-[2-(5-methyl-2-tert-butyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0526] IR v (nujol) cm⁻¹; 3458, 1682, 1618, 1587, 1510.

[0527]¹H-NMR (DMSO-d₆) δ (ppm);

[0528] 1.32 (9H, s), 2.23 (3H, s), 2.83 (2H, t, J=6.6 Hz), 3.18 (2H, d,J=5.9 Hz), 3.65-4.40 (7H, m), 5.60 (1H, br-s), 6.56 (1H, br-s), 6.73(1H, br-d), 7.06 (1H, d, J=8.4 Hz), 7.20-7.55 (5H, m).

EXAMPLE 332-Benzyl-7-[2-(5-methyl-2-(thiophen-2-yl)oxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0529] IR v (nujol) cm⁻¹; 3423, 1616, 1578, 1510.

[0530]¹H-NMR (DMSO-d₆) δ (ppm);

[0531] 2.31 (3H, s), 2.70-3.10 (4H, m), 3.40-4.00 (4H, m), 3.39 (2H, s),4.11 (2H, d, J=6.2 Hz), 6.59 (1H, br-s), 6.67 (1H, d, J=8.4 Hz), 7.01(1H, d, J=8.4 Hz), 7.05-7.80 (3H, m), 7.32 (5H, s).

EXAMPLE 342-Benzyl-7-[2-(5-methyl-2-isopropyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0532] IR v (nujol) cm⁻¹; 3456, 1684, 1614, 1576, 1510.

[0533]¹H-NMR (DMSO-d₆) δ (ppm);

[0534] 1.21 (6H, m), 2.19 (3H, s), 2.70-3.10 (5H, m), 3.50-4.20 (5H, m),6.40-6.85 (2H, m), 7.01 (1H, d, J=8.1 Hz), 7.34 (5H, br-s).

EXAMPLE 352-Butyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0535] IR v (nujol) cm⁻¹; 3382, 1722, 1614, 1554, 1506.

[0536]¹H-NMR (CDCl₃) δ (ppm);

[0537] 0.88 (3H, t, J=6.6 Hz), 1.10-1.95 (4H, m), 2.36 (3H, s),2.75-3.40 (6H, m), 3.71 (2H, br-t), 3.95-4.25 (4H, m), 6.57-7.57 (6H,m), 7.80-8.10 (3H, m).

EXAMPLE 362-Benzyl-7-{2-[5-methyl-2-(2-methylpropenyl)oxazol-4-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0538] IR v (nujol) cm⁻¹; 3443, 3300, 1695, 1655, 1622, 1543, 1508.

[0539]¹H-NMR (DMSO-d₆) δ (ppm);

[0540] 1.89 (3H, s), 2.11 (3H, s), 2.27 (3H, s), 2.79 (2H, t, J=6.1 Hz),2.90-3.20 (2H, m), 3.50-4.00 (4H, m), 3.93 (2H, s), 4.07 (2H, t, J=6.1Hz), 5.99 (1H, s), 6.58 (1H, s), 6.67 (1H, d, J=8.2 Hz), 6.72 (1H, d,J=8.2 Hz), 7.33 (5H, s).

EXAMPLE 372-Benzyl-7-{2-[2-(3-butenyl)-5-methyloxazol-4-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0541] IR v (nujol) cm⁻¹; 3442, 1688, 1614, 1578, 1508.

[0542]¹H-NMR (CDCl₃) δ (ppm);

[0543] 2.23 (3H, s), 2.49 (2H, t, J=6.2 Hz), 2.65-2.90 (4H, m),3.05-3.30 (2H, m), 3.75-4.50 (8H, m), 4.90-5.20 (2H, m), 5.65-6.10 (1H,m), 6.58 (1H, d, J=1.7 Hz), 6.75 (1H, dd, J=1.7, 8.2 Hz), 7.07 (1H, d,J=8.2 Hz), 7.35 (5H, s).

EXAMPLE 382-Allyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0544] IR v (nujol) cm⁻¹; 3335, 1690, 1618, 1553, 1506.

[0545]¹H-NMR (DMSO-d₆) δ (ppm);

[0546] 2.35 (3H, s), 2.70-3.15 (4H, m), 3.38 (2H, d, J=6.2 Hz),3.55-4.00 (3H, m), 4.16 (2H, t, J=6.6 Hz), 4.40-5.50 (1H, br), 5.00-5.40(2H, m), 5.60-6.10 (1H, m), 6.65 (1H, s), 6.69 (1H, d, J=8.1 Hz), 7.01(1H, d, J=8.1 Hz), 7.35-7.65 (3H, m), 7.75-8.10 (2H, m).

EXAMPLE 397-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-(2-propynyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0547] IR v (nujol) cm⁻¹; 3383, 3306, 3221, 1692, 1622, 1508.

[0548]¹H-NMR (DMSO-d₆) δ (ppm);

[0549] 2.00-6.40 (1H, br), 2.35 (3H, s), 2.70-3.10 (4H, m), 3.10-3.25(1H, m), 3.50-4.00 (5H, m), 4.17 (2H, t, J=6.4 Hz), 6.66 (1H, s), 6.70(1H, d, J=8.6 Hz), 7.01 (1H, d, J=8.6 Hz), 7.30-7.70 (3H, m), 7.85-8.05(2H, m).

EXAMPLE 402-(2-Butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0550] IR v (nujol) cm⁻¹; 3447, 3342, 1684, 1620, 1556.

[0551]¹H-NMR (DMSO-d₆) δ (ppm);

[0552] 1.67 (3H, d, J=4.9 Hz), 2.35 (3H, s), 2.70-3.10 (4H, m),3.20-3.50 (2H, m), 3.50-4.00 (3H, m), 4.16 (2H, t, J=6.4 Hz), 4.35-5.20(1H, br), 5.25-5.90 (2H, m), 6.55-6.90 (2H, m), 7.01 (2H, d, J=8.1 Hz),7.35-7.70 (3H, m), 7.75-8.10 (2H, m).

EXAMPLE 412-Benzyl-7-[(indolin-3-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0553] IR v (nujol) cm⁻¹; 1611, 1506.

[0554]¹H-NMR (DMSO-d₆) δ (ppm);

[0555] 1.60-2.30 (2H, m), 2.80-4.20 (10H, m), 3.91 (2H, s), 4.20-6.00(1H, br), 6.25-7.10 (7H, m), 7.33 (5H, s).

EXAMPLE 422-(3-Butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0556] IR v (nujol) cm⁻¹; 3425, 1682, 1612, 1555.

[0557]¹H-NMR (DMSO-d₆) δ (ppm);

[0558] 2.10-2.40 (2H, m), 2.35 (3H, s), 2.60-3.15 (6H, m), 3.50-4.00(3H, m), 4.17 (2H, t, J=6.3 Hz), 4.40-5.40 (1H, br), 4.85-5.25 (2H, m),5.55-6.10 (1H, m), 6.50-6.85 (2H, m), 7.01 (1H, d, J=8.1 Hz), 7.35-7.70(3H, m), 7.75-8.05 (2H, m).

EXAMPLE 437-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-pentanoyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0559] IR v (nujol) cm⁻¹; 1742, 1639, 1611, 1572, 1506.

[0560]¹H-NMR (DMSO-d₆) δ (ppm);

[0561] 0.88 (3H, br-t), 1.05-1.75 (4H, m), 2.15-2.70 (2H, m), 2.35 (3H,s), 2.70-3.30 (4H, m), 4.18 (2H, br-t), 4.30-4.90 (2H, m), 4.90-5.25(1H, m), 6.60-6.95 (2H, m), 7.08 (1H, d, J=7.9 Hz), 7.35-7.70 (3H, m),7.75-8.10 (2H, m), 11.00-13.00 (1H, br).

EXAMPLE 447-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-(4-pentenoyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0562] IR v (nujol) cm⁻¹; 1742, 1641, 1611, 1570.

[0563]¹H-NMR (DMSO-d₆) δ (ppm);

[0564] 2.15-2.70 (2H, m), 2.35 (3H, s), 2.70-3.30 (4H, m), 4.18 (2H,br-t), 4.37-5.50 (5H, m), 5.60-6.15 (1H, m), 6.60-6.95 (2H, m), 7.09(1H, d, J=7.7 Hz), 7.30-7.75 (3H, m), 7.75-8.15 (2H, m), 11.00-13.00(1H, br).

EXAMPLE 452-(3-Methyl-2-butenoyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0565] IR v (nujol) cm⁻¹; 1738, 1641, 1611, 1555.

[0566]¹H-NMR (DMSO-d₆) δ (ppm);

[0567] 1.87 (6H, s), 2.35 (3H, s), 2.70-3.30 (4H, m), 4.18 (2H, br-t),4.49 (1H, d, J=18.0 Hz), 4.76 (1H, d, J=18.0 Hz), 4.95-5.22 (1H, m),5.75-6.10 (1H, m), 6.50-6.90 (2H, m), 7.08 (1H, d, J=7.5Hz), 7.20-7.60(3H, m), 7.60-8.05 (2H, m), 11.00-13.00 (1H, br).

EXAMPLE 462-(3,3-Dimethylbutyryl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0568] IR v (nujol) cm⁻¹; 1738, 1639, 1611, 1583, 1555.

[0569]¹H-NMR (DMSO-d₆) δ (ppm);

[0570] 1.02 (9H, s), 2.36 (5H, s), 2.73-3.20 (4H, m), 4.17 (2H, t, J=7.0Hz), 4.50 (1H, d, J=9.0 Hz), 4.83 (1H, d, J=9.0 Hz), 5.12 (1H, t, J=6.0Hz), 6.60-6.95 (2H, m), 7.10 (1H, d, J=7.0 Hz), 7.35-7.65 (3H, m),7.80-8.05 (2H, m), 11.00-13.00 (1H, br).

EXAMPLE 472-Benzyl-7-methoxy-6-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3RS)-carboxylicacid

[0571] IR v (nujol) cm⁻¹; 1722, 1628, 1553, 1520.

[0572]¹H-NMR (DMSO-d₆) δ (ppm);

[0573] 2.36 (3H, s), 3.00 (2H, t, J=6.8 Hz), 3.10-3.35 (2H, m),3.80-4.10 (3H, m), 3.75 (3H, s), 4.23 (2H, t, J=6.8 Hz), 5.80-6.20 (1H,br), 6.50, 6.72 (2H, s, s), 7.20-7.60 (8H, m), 7.80-8.10 (2H, m).

EXAMPLE 48 Sodium7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0574] IR v (nujol) cm⁻¹; 1609, 1575, 1554, 1502.

[0575]¹H-NMR (CDCl₃) δ (ppm);

[0576] 2.32 (3H, s), 2.60-3.20 (4H, m), 3.20-3.90 (5H, m), 4.08 (2H,br-t, J=6.5 Hz), 6.15-6.40 (1H, m), 6.40-6.70 (1H, m), 7.75-8.20 (3H,m), 7.20-7.65 (4H, m), 7.75-8.10 (2H, m), 8.25-8.60 (1H, m).

EXAMPLE 492-Benzyl-7-(3-methyl-3-phenylbutoxy)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0577] IR v (nujol) cm⁻¹; 1612, 1506.

[0578]¹H-NMR (DMSO-d₆) δ (ppm);

[0579] 1.32 (6H, s), 2.02 (2H, t, J=7.5 Hz), 2.80-3.10 (2H, m),3.40-4.00 (5H, m), 3.88 (2H, s), 4.10-6.00 (1H, br), 6.36 (1H, d, J=2.0Hz), 6.53 (1H, dd, J=2.0, 8.6 Hz), 6.96 (1H, d, J=8.6 Hz), 7.10-7.55(10H, m).

EXAMPLE 502-Benzyl-7-(3,3-dimethyl-4-phenylbutoxy)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0580] IR v (nujol) cm⁻¹; 1611, 1506.

[0581]¹H-NMR (DMSO-d₆) δ (ppm);

[0582] 0.87 (6H, S), 1.61 (2H, t, J=7.0 Hz), 2.54 (2H, s), 2.85-3.15(2H, m), 3.50-4.20 (5H, m), 3.91 (2H, s), 4.20-6.00 (1H, br), 6.60 (1H,br-s), 6.67 (1H, d, J=8.6 Hz), 7.01 (1H, d, J=8.6 Hz), 7.05-7.50 (10H,m).

EXAMPLE 512-Benzyl-7-(2-isopropylbenzoxazol-6-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0583] IR v (Nujol) cm⁻¹; 1632, 1585, 1572, 1501.

[0584]¹H-NMR (DMSO-d₆) δ (ppm);

[0585] 1.37 (6H, d, J=7.0 Hz), 2.85-3.45 (4H, m), 3.50-4.20 (6H, m),5.12 (2H, s), 6.69 (1H, s), 6.77 (1H, d, J=8.6 Hz), 7.04 (1H, d, J=8.6Hz), 7.25-7.85 (8H, m).

EXAMPLE 522-Benzyl-7-(2-tert-butylbenzoxazol-6-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0586] IR v (Nujol) cm⁻¹; 1611, 1583, 1562, 1506.

[0587]¹H-NMR (DMSO-d₆) δ (ppm);

[0588] 1.42 (9H, s), 2.85-3.10 (2H, br), 3.50-4.20 (6H, m), 5.13 (2H,s), 6.70 (1H, s), 6.77 (1H, d, J=8.4 Hz), 7.04 (1H, d, J=8.4 Hz),7.20-7.50 (6H, m), 7.55-7.65 (1H, m), 7.70 (1H, s).

EXAMPLE 532-Benzyl-7-(2-tert-butylbenzoxazol-5-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0589] IR v (nujol) cm⁻¹; 1717, 1645, 1612, 1553.

[0590]¹H-NMR (DMSO-d₆) δ (ppm );

[0591] 1.43 (9H, s), 2.85-3.15 (2H, m), 3.50-4.15 (3H, m), 3.90 (2H, s),5.11 (2H, s), 6.69 (1H, br-s), 6.75 (1H, d, J=8.1 Hz), 7.03 (1H, d,J=8.1 Hz), 7.10-7.50 (6H, m), 7.65 (1H, d, J=9.0), 7.71 (1H, br-s).

EXAMPLE 547-(2-tert-Butylbenzoxazol-6-yl)methoxy-2-(2,2-dimethylpropyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0592] IR v (nujol) cm⁻¹; 1740, 1612, 1560, 1508.

[0593]¹H-NMR (DMSO-d₆) δ (ppm);

[0594] 1.10 (9H, s), 1.43 (9H, s), 2.79, 3.19 (2H, ABq, J=13.6 Hz),3.20-3.45 (3H, m), 4.25-4.55 (4H, br), 5.20 (2H, s), 6.96 (1H, d, J=8.1Hz), 7.00 (1H, s), 7.20 (1H, d, J=8.1 Hz), 7.40 (1H, d, J=8.1 Hz), 7.68(1H, d, J=8.1 Hz), 7.73 (1H, s).

EXAMPLE 552-Benzyl-7-(2-isopropylbenzoxazol-5-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0595] IR v (nujol) cm⁻¹; 1634, 1587, 1570, 1501.

[0596]¹H-NMR (DMSO-d₆) δ (ppm);

[0597] 1.37 (6H, d, J=6.8 Hz), 2.90-3.15 (2H, m), 3.25 (1H, quintet,J=6.8 Hz), 3.50-4.30 (7H, m), 5.11 (2H, s), 6.69 (1H, s), 6.76 (1H, d,J=8.1 Hz), 7.04 (1H, d, J=8.1 Hz), 7.20-7.50 (6H, m), 7.55-7.65 (1H, m),7.70 (1H, s).

EXAMPLE 56 Sodium7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0598] IR v (nujol) cm⁻¹; 3420, 3177, 1639, 1558, 1504.

[0599]¹H-NMR (DMSO-d₆) δ (ppm);

[0600] 2.34 (3H, s), 2.70-3.05 (4H, m), 3.10-3.60 (3H, m), 3.98 (2H,br-t, J=5.7 Hz), 4.10-4.25 (2H, m), 6.51 (1H, br-s), 6.61 (1H, br-d,J=8.7 Hz), 6.94 (1H, br-d, J=8.7 Hz), 7.25-7.65 (5H, m), 7.75-8.00 (2H,m), 8.46 (2H, d, J=5.2 Hz).

EXAMPLE 57 Sodium7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-[(pyridin-2-yl)carbonyl]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0601] IR v (nujol) cm⁻¹; 3385, 1624, 1566, 1504.

[0602]¹H-NMR (MeOH-d₄) δ (ppm);

[0603] 2.31, 2.36 (3H, s, s), 2.75-3.05 (2H, m), 3.05-3.30 (2H, m),4.00-4.30 (2H, m), 4.50-5.30 (3H, m), 6.60-6.80 (2H, m) 7.03 (1H, dd,J=2.0, 8.5 Hz), 7.30-7.75 (5H, m), 7.75-8.10 (3H, m), 8.50-8.70 (1H, m).

EXAMPLE 58 Methyl2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0604] IR v (nujol) cm⁻¹; 1736, 1639, 1612, 1504.

[0605]¹H-NMR (CDCl₃) δ (ppm);

[0606] 2.34 (3H, s), 2.92 (2H, t, J=7.0 Hz), 3.07 (2H, d, J=5.0 Hz),3.64 (3H, s), 3.64-4.00 (5H, m), 4.17 (2H, t, J=7.0 Hz), 6.51 (1H, d,J=2.0 Hz), 6.68 (1H, dd, J=2.0, 8.4 Hz), 6.98 (1H, d, J=8.4 Hz),7.20-7.60 (8H, m), 7.80-8.10 (2H, m).

EXAMPLE 592-Benzyl-7-[2-(2-cyclopropyl-5-methyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0607] IR v (nujol) cm⁻¹; 3470, 1684, 1618, 1583, 1510.

[0608]¹H-NMR (DMSO-d₆) δ (ppm);

[0609] 0.70-1.10 (4H, m), 1.80-2.20 (1H, m), 2.16 (3H, s), 2.60-2.85(2H, m), 2.90-3.15 (2H, m), 3.50-4.20 (5H, m), 6.50-6.80 (2H, m), 7.03(1H, d, J=8.1 Hz), 7.34 (5H, s).

EXAMPLE 602-(3-Methyl-2-butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0610] IR v (nujol) cm⁻¹; 3447, 3335, 1670, 1668, 1622, 1556, 1506.

[0611]¹H-NMR (DMSO-d₆) δ (ppm);

[0612] 1.61 (3H, s), 1.72 (3H, s), 2.35 (3H, s), 2.70-3.20 (4H, m), 3.39(2H, d, J=7.0 Hz), 3.50-4.01 (3H, m), 4.16(2H, t, J=7.0 Hz), 4.35-5.60(1H, br), 5.25 (1H, br-t), 6.67 (1H, s), 6.71 (1H, d, J=8.4 Hz), 7.02(1H, d, J=8.4 Hz), 7.30-7.70 (8H, m), 7.75-8.10 (2H, m).

EXAMPLE 612-(2,2-Dimethylpropyl)-7-[2-(5-methyl-2-tert-butyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0613] IR v (nujol) cm⁻¹; 1717, 1614, 1566, 1504.

[0614]¹H-NMR (CDCl₃) δ (ppm);

[0615] 0.97 (9H, s), 1.33 (9H, s), 2.24 (3H, s), 2.44, 2.68 (2H, ABq,J=13.9 Hz), 2.84 (2H, t, J=6.7 Hz), 3.00-3.22 (2H, m), 3.65 (3H, t,J=6.1 Hz), 3.83, 4.08 (2H, ABq, J=15.1 Hz), 4.07 (2H, t, J=6.7 Hz), 6.58(1H, d, J=1.7 Hz), 6.72 (1H, dd, J=1.7, 8.4 Hz), 7.05 (1H, d, J=8.4 Hz),7.50-8.20 (1H, br).

EXAMPLE 622-Benzyl-7-[2-(1-butenyl)-5-methyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0616] IR v (nujol) cm⁻¹; 3470, 1682, 1614, 1585, 1512.

[0617]¹H-NMR (CDCl₃) δ (ppm);

[0618] 1.07 (3H, t, J=7.5 Hz), 2.05-2.20 (1H, m), 2.26 (3H, s),2.50-3.00 (3H, m), 3.65-4.45 (7H, m), 5.92 (1H, br-s), 6.17 (1H, d,J=16.3 Hz), 6.45-6.85 (3H, m), 7.05 (1H, d, J=8.4 Hz), 7.34 (5H, s).

EXAMPLE 632-Benzyl-7-[2-(2,2-dimethylpropyl)-5-methyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0619] IR v (nujol) cm⁻¹; 1722, 1614, 1568, 1506.

[0620]¹H-NMR (CDCl₃) δ (ppm);

[0621] 0.95 (9H, s), 2.34 (3H, s), 2.55 (2H, s), 2.60-3.00 (2H, m),3.00-3.30 (2H, m), 3.80-4.40 (7H, m), 6.64 (1H, br-s), 6.70 (1H, d,J=8.8 Hz), 7.02 (1H, d, J=8.8 Hz), 7.32 (5H, s), 7.80 (1H, br-s).

EXAMPLE 64 Ethyl2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylatehydrochloride

[0622] IR v (nujol) cm⁻¹; 3400, 1744, 1676, 1614, 1589, 1574, 1553,1508.

[0623]¹H-NMR (DMSO-d₆) δ (ppm);

[0624] 1.12 (9H, s), 1.23 (3H, t, J=7.0 Hz), 2.36 (3H, s), 2.60-3.60(6H, m), 4.00-4.40 (4H, m), 4.40-6.00 (4H, m), 6.88 (1H, d, J=8.0 Hz),6.92(1H, s), 7.18 (1H, d, J=8.0 Hz), 7.35-7.70 (8H, m), 7.75-8.10 (2H,m).

EXAMPLE 657-(Benzofran-2-ylmethoxy)-2-benzyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0625] IR v (nujol) cm⁻¹; 1632, 1587, 1501.

[0626]¹H-NMR (DMSO-d₆) a (ppm);

[0627] 2.00-6.50 (1H, br), 2.85-3.15 (2H, m), 3.50-4.10 (3H, m), 3.91(2H, s), 5.16 (2H,s), 6.60-7.80 (8H, m), 7.33 (5H,s).

EXAMPLE 662-Isobutyryl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0628] IR v (nujol) cm⁻¹; 1736, 1639, 1612, 1504.

[0629]¹H-NMR (DMSO-d₆) δ (ppm);

[0630] 1.02 (6H, br-d), 2.35 (3H, s), 2.65-3.30 (5H, m), 4.00-5.30 (6H,m), 6.60-6.95 (2H, m), 7.09 (1H, d, J=8.0 Hz), 7.25-7.70 (8H, m),7.70-8.10 (2H, m).

EXAMPLE 677-[2-(Benzofran-2-yl)ethoxy]-2-benzyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0631] IR v (nujol) cm⁻¹; 1634, 1585, 1501.

[0632]¹H-NMR (DMSO-d₆) δ (ppm);

[0633] 2.80-3.10 (2H, m), 3.19 (2H, br-t), 3.45-4.10 (3H, m), 3.90(2H,s), 4.25 (2H, br-t), 6.50-7.80 (9H, m), 7.33 (5H, s).

EXAMPLE 687-[2-(5-Ethylpyridin-2-yl)ethoxy]-2-hexanoyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid hydrochloride

[0634]¹H-NMR (CDCl₃) δ (ppm);

[0635] 0.87 (3H, br-t), 1.05-1.85 (9H, m), 2.15-2.55 (4H, m), 2.55-3.75(4H, m), 4.00-4.90 (4H, m), 5.25-5.50 (1H, m), 6.40-7.10 (4H, m), 7.75(1H, br-d), 8.15 (1H, br-d), 8.52 (1H, br-s).

EXAMPLE 692-Carboxymethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0636] IR v (nujol) cm⁻¹; 1620, 1585, 1556, 1508.

[0637]¹H-NMR (DMSO-d₆) δ (ppm);

[0638] 2.35 (3H, s), 2.70-3.15 (4H, m), 3.41, 3.65 (2H, ABq, J=17.5 Hz),3.70-4.00 (3H, m), 4.16 (2H, t, J=7.0 Hz), 6.00-11.00 (1H, br), 6.64(1H, s), 6.69 (1H, d, J=8.2 Hz), 7.01 (1H, d, J=8.2 Hz), 7.20-7.70 (8H,m), 7.70-8.05 (2H, m).

EXAMPLE 702-[3-(Methoxycarbonyl)propionyl]-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0639] IR v (nujol) cm⁻¹; 1732, 1652, 1554, 1505.

[0640]¹H-NMR (CDCl₃) δ (ppm);

[0641] 2.33 (3H, s), 2.50-3.40 (7H, m), 3.65 (3H, s), 4.07 (2H, br-t),4.45-5.50 (3H, m), 5.60-6.20 (1H, br), 6.59 (1H, br-s), 6.67 (1H, d,J=8.0 Hz), 7.03 (1H, d, J=8.0 Hz), 7.20-7.60 (3H, m), 7.80-8.10 (2H, m).

EXAMPLE 712-[3-(Ethoxycarbonyl)propyl]-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0642] IR v (nujol) cm⁻¹; 3375, 1733, 1620, 1555, 1505.

[0643]¹H-NMR (CDCl₃) δ (ppm);

[0644] 1.18 (3H, t, J=7.0 Hz), 1.76-2.15 (2H, m), 2.15-2.50 (2H, m),2.35 (3H, s), 2.70-3.35 (6H, m), 3.60-4.40 (7H, m), 5.27 (1H, br-s),6.61(1H, br-s), 6.73 (1H, d, J=8.4 Hz), 7.03 (1H, d, J=8.4 Hz),7.25-7.55 (3H, m), 7.80-8.10 (2H, m).

EXAMPLE 722-Benzyl-6-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3RS)-carboxylicacid

[0645] IR v (nujol) cm⁻¹; 1634, 1614, 1499.

[0646]¹H-NMR (DMSO-d₆) δ (ppm);

[0647] 2.35 (3H, s), 2.65-3.25 (4H, m), 3.40-4.00 (3H, m), 3.90 (2H, s),4.17 (2H, br-t), 6.20-10.00 (1H, br), 6.50-7.00 (2H, m), 6.71 (1H, s),7.30-7.70 (3H, m), 7.32 (5H, s), 7.75-8.15 (2H, m).

EXAMPLE 732-(3-Acetylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0648] IR v (nujol) cm⁻¹; 1682, 1620, 1508.

[0649]¹H-NMR (DMSO-d₆) δ (ppm);

[0650] 2.33 (3H, s), 2.56 (3H, s), 2.70-3.20 (4H, m), 3.50-4.30 (5H, m),3.97 (2H, s), 6.50-6.90 (2H, m), 7.02 (1H, d, J=8.4 Hz), 7.30-8.00 (9H,m).

EXAMPLE 742-(2-Acetylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0651] IR v (nujol) cm⁻¹; 1668, 1643, 1614, 1504.

[0652]¹H-NMR (DMSO-d₆) δ (ppm);

[0653] 2.33 (3H, s), 2.36 (3H, s), 2.70-3.20 (4H, m), 3.30-4.30 (5H, m),6.57 (1H, d, J=2.0 Hz), 6.66 (1H, dd, J=2.0, 8.4 Hz), 7.00 (1H, d, J=8.4Hz), 7.20-7.75 (7H, m), 7.75-8.10 (2H, m).

EXAMPLE 752-Benzyl-7-[(5-methyl-2-phenyloxazol-4-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid

[0654] IR v (nujol) cm⁻¹; 3462, 1680, 1614, 1556, 1508.

[0655]¹H-NMR (DMSO-d₆) δ (ppm);

[0656] 2.41 (3H, s), 2.83-3.20 (2H, m), 3.44-4.20 (5H, m), 4.91 (2H, s),6.73 (1H, br-s), 6.77 (1H, d, J=8.1 Hz), 7.34 (1H, d, J=8.1 Hz), 7.34(5H, s), 7.40-7.68 (3H, m), 7.75-8.10 (2H, m).

Reference Example 1 Ethyl2-tert-butoxycarbonyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0657] (1) 3,5-Diiodo-L-tyrosine dihydrate (25.0 g) was suspended inconcentrated hydrochloric acid (250 ml). Thereto were successively added1,2-dimethoxyethane (18 ml) and 37% formalin (20 ml), and the mixturewas warmed to 75° C. over 30 min. To the reaction mixture were furtheradded concentrated hydrochloric acid (120 ml), 1,2-dimethoxyethane (9ml) and 37% formalin (10 ml), and the mixture was stirred at 75° C. for18 hr. The precipitated crystals were collected by filtration and washedwith 1,2-dimethoxyethane (20 ml) to give7-hydroxy-6,8-diiodo-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acidhydrochloride (12.8 g).

7-Hydroxy-6,8-diiodo-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acidhydrochloride

[0658] IR v (nujol) cm⁻¹; 1751, 1599, 1578.

[0659]¹H-NMR (CDCl₃) δ (ppm);

[0660] 3.00-3.30 (2H, m), 4.05 (2H, s), 4.30 (1H, dd, J=5.9, 9.5 Hz),7.71 (1H, s).

[0661] (2) The compound (12.8 g) obtained in (1) above was suspended inethanol (500 ml). Thereto was added concentrated hydrochloric acid (10ml) and the mixture was refluxed for 15 hr. Ethanol was evaporated underreduced pressure. Ethyl acetate (300 ml) was added to the obtainedresidue, and the compound was washed with saturated aqueous sodiumhydrogencarbonate solution (100 ml) and saturated brine (100 ml) anddried over Na₂SO₄. Ethyl acetate was evaporated under reduced pressureto give ethyl7-hydroxy-6,8-diiodo-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate(11.11 g).

Ethyl7-hydroxy-6,8-diiodo-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0662]¹H-NMR (CDCl₃) δ (ppm);

[0663] 1.29 (3H, t, J=7.0 Hz), 2.80-3.00 (2H, m), 3.30-4.10 (5H, m),4.23 (2H, q, J=7.0 Hz), 7.46 (1H, s).

[0664] (3) 10% Pd-C (350 mg) was suspended in methanol (60 ml). Theretowere added triethylamine (2.0 ml) and the compound (2.80 g) obtained in(2) above, and the compound was catalytically hydrogenated at roomtemperature, 29.4×10⁴ Pa (3.0 kgf/cm²) for 3 hr. Pd-C was filtered off,and methanol was evaporated under reduced pressure. Ethyl acetate (10ml) was added to the obtained residue. The mixture was washed withsaturated brine (100 ml) and dried over Na₂SO₄. Ethyl acetate wasevaporated under reduced pressure to give ethyl7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1.14 g).

Ethyl 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0665]

[0666] IR v (nujol) cm⁻¹; 1732, 1607, 1516.

[0667]¹H-NMR (CDCl₃) δ (ppm);

[0668] 1.28 (3H, t, J=7.0 Hz), 2.80-3.10 (3H, m), 3.60-3.80 (1H, m),3.97 (2H, s), 4.05-4.20 (4H, m), 6.43 (1H, s), 6.50-6.80 (1H, m), 6.92(1H, d, J=8.4 Hz).

[0669] (4) The compound (1.13 g) obtained in (3) above was dissolved intetrahydrofuran (20 ml). Thereto was added di-tert-butyl dicarbonate(1.50 g) and the mixture was stirred at room temperature for 1 hr. Ethylacetate (30 ml) was added to the reaction mixture, and the mixture waswashed with saturated brine (20 ml) and dried over Na₂SO₄. Ethyl acetatewas evaporated under reduced pressure. The obtained residue was purifiedby column chromatography to give the title compound (1.51 g).

[0670] IR v (nujol) cm⁻¹; 3260, 1756, 1671, 1615, 1506.

[0671]¹H-NMR (CDCl₃) δ (ppm);

[0672] 1.29 (3H, t, J=7.0 Hz), 1.47 (9H, s), 3.08 (2H, d, J=5.2 Hz),4.21 (2H, q, J=7.0 Hz), 4.41 (1H, d, J=15.5 Hz), 4.60-5.25 (1H, m), 4.65(1H, d, J=15.5 Hz), 5.00-6.00 (1H, br), 6.50-6.80 (2H, m), 6.98 (1H, d,J=8.1 Hz).

Reference Example 2 Methyl 2-tert-butoxycarbonyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0673] In the same manner as in Reference Example 1, the title compoundwas obtained.

[0674] IR v (nujol) cm⁻¹; 3261, 1755, 1672, 1614, 1506.

[0675]¹H-NMR (CDCl₃) δ (ppm);

[0676] 1.47 (9H, s), 3.08 (2H, d, J=5.2 Hz), 3.63 (3H, s), 4.40 (1H, d,J=16.5 Hz), 4.60-5.25 (1H, m), 4.66 (1H, d, J=16.5 Hz), 5.60-6.60 (1H,br), 6.50-6.80 (2H, m), 6.99 (1H, d, J=8.1 Hz).

Reference Example 3 2-(5-Methyl-2-phenyl-oxazol-4-yl)ethylmethanesulfonate

[0677] To methylene chloride (200 ml) were added2-(5-methyl-2-phenyl-oxazol-4-yl)ethanol (20 g) and triethylamine (19.2ml). Thereto was dropwise added methanesulfonyl chloride (9.52 ml) at 0°C. and the mixture was stirred at the same temperature for 15 min. Themixture was washed with 10% aqueous citric acid solution (200 ml),saturated aqueous sodium hydrogencarbonate solution (100 ml) andsaturated brine (100 ml) and dried over Na₂SO₄. Methylene chloride wasevaporated under reduced pressure. The obtained residue was purified bycolumn chromatography to give the title compound (21.45 g).

[0678]¹H-NMR (CDCl₃) δ (ppm);

[0679] 2.53 (3H, s), 2.94 (3H, s), 2.94 (2H, t, J=7.0 Hz), 4.52 (2H, t,J=7.0 Hz), 7.30-7.50 (3H, m), 7.80-8.10 (2H, m).

Reference Example 4 Ethyl2-benzyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

[0680] The compound (8.1 g) obtained in Reference Example 1(3) wasdissolved in N,N-dimethylformamide (80 ml). Thereto were addedtriethylamine (2.0 ml) and benzyl bromide (4.57 ml) and the mixture wasstirred at room temperature for 3 hr. Water (500 ml) was added to thereaction mixture, and the mixture was extracted twice with ethyl acetate(200 ml). The combined ethyl acetate layer was washed with saturatedbrine (500 ml) and dried over Na₂SO₄. Ethyl acetate was evaporated underreduced pressure. The obtained residue was purified by columnchromatography to give the title compound (10.46 g).

[0681] IR v (nujol) cm⁻¹; 3410, 1717, 1624, 1506.

[0682]¹H-NMR (CDCl₃) δ (ppm);

[0683] 1.22 (3H, t, J=7.0 Hz), 3.06 (2H, d, J=5.0 Hz), 3.66 (1H, t,J=5.0 Hz), 3.78 (2H, s), 3.90 (2H, s), 4.13 (2H, q, J=7.0 Hz), 6.37 (1H,d, J=2.0 Hz), 6.56 (1H, dd, J=2.0, 8.4 Hz), 6.92 (1H, d, J=8.4 Hz),7.20-7.50 (5H, m).

Reference Example 5 2-(N-tert-Butoxycarbonyl-N-methylamino)ethylmethanesulfonate

[0684] (1) 2-(Methylamino)ethanol (3.5 ml) was dissolved intetrahydrofuran (150 ml). Thereto was added di-tert-butyl dicarbonate(12.5 g) and the mixture was stirred at room temperature for 20 min.Tetrahydrofuran was evaporated under reduced pressure. The obtainedresidue was purified by column chromatography to give2-(N-tert-butoxycarbonyl-N-methylamino)ethanol (6.35 g).

[0685] 2-(N-tert-Butoxycarbonyl-N-methylamino)ethanol

[0686] IR v(neat) cm⁻¹; 3423, 2976, 2934, 2882, 1674.

[0687]¹H-NMR (CDCl₃) δ (ppm);

[0688] 1.43 (9H, s), 2.89 (3H, s), 3.34 (2H, t, J=5.8 Hz), 3.67 (2H, t,J=5.8 Hz), 4.00-6.00 (1H, br).

[0689] (2) The compound (505 mg) obtained in (1) above was dissolved inmethylene chloride (20 ml). Thereto were added triethylamine (0.5 ml)and methanesulfonyl chloride (0.25 ml) and the mixture was stirred atroom temperature for 1 hr. Methylene chloride (30 ml) was added to themixture, and the mixture was washed with saturated brine (20 ml) anddried over Na₂SO₄. Methylene chloride was evaporated under reducedpressure to give the title compound (720 mg).

[0690]¹H-NMR (CDCl₃) δ (ppm);

[0691] 1.46 (9H, s), 2.94 (3H, s), 3.01 (3H, s), 3.54 (2H, t, J=5.5 Hz),4.33 (2H, t, J=5.5 Hz).

Reference Example 6 1-(2-Bromoethyl)indoline

[0692] To 1,2-dibromoethane (58.0 ml) were added indoline (5.0 g) andtriethylamine (28.7 ml), and the mixture was stirred at 90° C. for 2 hr.Ethyl acetate (200 ml) was added to the reaction mixture, and themixture was washed with saturated brine (400 ml) and dried over Na₂SO₄.Ethyl acetate was evaporated under reduced pressure. The obtainedresidue was purified by column chromatography to give the title compound(4.09 g).

[0693] IR v(neat) cm⁻¹; 2924, 2845, 1607, 1489.

[0694]¹H-NMR (CDCl₃) δ (ppm);

[0695] 2.99 (1H, t, J=8.4 Hz), 3.45 (1H, t, J=8.4 Hz), 3.49 (4H, s),6.40-6.75 (2H, m), 6.90-7.20 (2H, m).

Reference Example 7 1-(2-Bromoethyl)-6-methoxycarbonylindoline

[0696] To 1,2-dibromoethane (15.7 ml) were added6-methoxycarbonylindoline (2.41 g) and triethylamine (7.8 ml), and themixture was stirred at 90° C. for 2 hr. Ethyl acetate (150 ml) was addedto the reaction mixture, and the mixture was washed with saturated brine(300 ml) and dried over Na₂SO₄. Ethyl acetate was evaporated underreduced pressure. The obtained residue was purified by columnchromatography to give the title compound (1.71 g).

[0697] IR v(neat) cm⁻¹; 1713, 1611, 1499.

[0698]¹H-NMR (CDCl₃) δ (ppm);

[0699] 3.03 (1H, t, J=8.4 Hz), 3.53 (1H, t, J=8.4 Hz), 3.53 (4H, s),3.88 (3H, s), 6.00-6.20 (2H, m), 7.39 (1H, dd, J=1.5, 7.8 Hz).

Experimental Example 1 Hypoglycemic Action (Method A)

[0700] Blood was drawn under a non-fasting state from the tail vein ofmale KK-A^(y) mice, which were spontaneously diabetic models, haddeveloped diabetes due to insulin resistance and which showedhyperglycemia and hyperinsulinemia. The glucose level in the plasma wasmeasured using a commercially available assay kit (glucose CII-testWAKO, Wako Pure Chemical Industries, Ltd.). The mice were grouped (5mice per group) into a control group and an administration group, suchthat the mean and the standard deviation of the glucose level in theplasma of each group were nearly the same. Each test compound wassuspended or dissolved in 5% gum arabic solution and administered orallyto the administration group for 4 consecutive days from the next day.The 5% gum arabic solution was orally administered to the control group.Blood was drawn from the tail vein under a non-fasting state about 24hours after the final administration and the glucose level in the plasmawas measured. The decrease in the plasma glucose level was calculatedfrom the following formula. The results are shown in Table 1.

Decrease (%) in plasma glucose level=[(mean plasma glucose level ofcontrol group−mean plasma glucose level of test compound administrationgroup)/mean plasma glucose level of control group]×100

[0701] TABLE 1 Hypoglycemic action (method A) Decrease (%) in plasmaTest Dose glucose compound (mg/kg) level Example 2 10 38.3 30 60.6Example 3 30 11.8 Example 5 10 34.1 30 43.4 Example 6 10 10.7 30 12.2Example 7 10 11.4 30 17.4 Example 9 30 20.3 Example 12 10 12.0 Example16 30 34.5 Example 18 30 39.7 Example 21 30 43.4 Example 23 10 24.3 3042.9 Example 32 30 36.4 Example 33 30 38.8 Example 34 30 23.5 Example 3530 22.1 Example 36 30 28.4 Example 37 30 11.1 Example 38 30 28.0 Example39 30 30.7 Example 40 30 46.3 Example 41 30 11.1 Example 42 10 27.6 3049.6 Example 43 30 27.5 Example 44 30 48.0 Example 45 30 12.6 Example 4630 28.6 Example 48 30 16.1 Example 49 30 11.1 Example 50 30 11.4 Example51 30 20.0 Example 52 30 26.3 Example 53 30 13.6 Example 54 30 10.8Example 55 30 13.9 Example 58 30 19.1 Example 67 30 10.6 Example 69 3012.5 Example 70 30 15.2 Example 71 30 10.5 Example 72 30 15.9 Example 7330 14.8

Experimental Example 2 Hypoglycemic Action (Method B)

[0702] Blood was drawn under a non-fasting state from the tail vein ofmale KK-A^(y) mice, which were spontaneously diabetic models, haddeveloped diabetes due to insulin resistance and which showedhyperglucemia and hyperinsulemia. The glucose level in the plasma wasmeasured using a commercially available assay kit (glucose CII-testWAKO, Wako Pure Chemical Industries, Ltd.). The mice were grouped (5mice per group) into a control group and an administration group, suchthat the mean and the standard deviation of the glucose level in theplasma of each group were nearly the same. Each test compound wasadmixed in a proportion of 0.1 w/w % with a powder feed (CE-2, Clea) andthe feed mixture was fed to the administration group for 4 days from thenext day. A regular powder feed was fed to the control group. At day 5,blood was drawn from the tail vein under a non-fasting state and theglucose level in the plasma was measured. The decrease in the plasmaglucose level was calculated from the following formula. The results areshown in Table 2.

Decrease (%) in plasma glucose level=[(mean plasma glucose level ofcontrol group−mean plasma glucose level of test compound administrationgroup)/mean plasma glucose level of control group]×100

[0703] TABLE 2 Hypoglycemic action (method B) Decrease (%) in plasmaTest compound glucose level Example 2 69.2 Example 10 42.4

Experimental Example 3 Hypotriglyceridemic Action

[0704] Blood was drawn under a non-fasting state from the tail vein ofmale KK-A^(y) mice, which were spontaneously diabetic models, haddeveloped diabetes due to insulin resistance, and which showedhyperglycemia and hyperinsulinemia. The triglyceride level in the plasmawas measured using a commercially available assay kit (triglycerideG-test WAKO, Wako Pure Chemical Industries, Ltd.). The mice were grouped(5 mice per group) into a control group and an administration group,such that the mean and the standard deviation of the triglyceride levelin the plasma of each group were nearly the same. Each test compound wassuspended or dissolved in 5% gum arabic solution and administered orallyto the administration group for 4 consecutive days from the next day.The 5% gum arabic solution was orally administered to the control group.Blood was drawn from the tail vein under a non-fasting state about 24hours after the final administration and the triglyceride level in theplasma was measured. The decrease in the plasma triglyceride level wascalculated from the following formula. The results are shown in Table 3.

Decrease (%) in plasma triglyceride level=[(mean plasma triglyceridelevel of control group−mean plasma triglyceride level of test compoundadministration group)/mean plasma triglyceride level of controlgroup]×100

[0705] TABLE 3 hypotriglyceridemic action Decrease (%) in plasma tri-Test Dose glyceride compound (mg/kg) level Example 2 10 39.5 30 54.3Example 4 10 14.3 Example 5 30 30.9 Example 11 10 11.2 Example 12 1022.9 Example 16 30 19.8 Example 18 30 45.5 Example 21 30 24.4 Example 2310 30.4 30 50.4 Example 32 30 32.5 Example 33 30 42.0 Example 34 30 17.3Example 35 30 12.4 Example 36 30 13.7 Example 38 30 30.0 Example 39 3015.6 Example 40 30 36.1 Example 42 30 31.6 Example 43 30 20.9 Example 4430 19.1 Example 49 30 17.0 Example 50 30 35.7 Example 51 30 10.7 Example52 30 26.6 Example 56 30 14.0 Example 58 30 24.7 Example 59 30 13.7Example 69 30 15.2 Example 72 30 24.0 Example 73 30 15.4

Experimental Example 4 Hypoglycemic Action and Hypoinsulinemic Action inInsulin Resistant Diabetic Mouse

[0706] The insulin resistance improving action was examined in KK-A^(y)mice, which were spontaneously diabetic models, had developed diabetesdue to insulin resistance, and which showed hyperglycemia andhyperinsulinemia. Blood was drawn from the tail vein of 12-week-old maleKK-A^(y) mice under a non-fasting state, and the glucose level in theplasma was measured using a commercially available assay kit (glucoseCII-test WAKO, Wako Pure Chemical Industries, Ltd.). The mice weregrouped (5 mice per group) into a control group and an administrationgroup, such that the mean glucose level in the plasma and the averagebody weight of each group, as well as the standard deviation thereofwere nearly the same. The test compound (10 mg/kg) was suspended in 5%aqueous gum arabic solution and orally administered once a day to theadministration group for 4 days from the next day. The 5% aqueous gumarabic solution was orally administered to the control group. Blood wasdrawn from the tail vein under a non-fasting state 24 hours after thefinal administration. The concentrations of plasma glucose and plasmainsulin were measured. The results are shown in Table 4.

[0707] As a result, each test compound (10 mg/kg) lowered the glucoselevel in plasma and also decreased the insulin concentration in plasma.This means that the test compound lowered the plasma glucose level notby insulin secretion but by insulin sensitivity potentiating action(insulin resistance improving action), thereby to improvehyperinsulinemia. TABLE 4 Hypoglycemic action and Hypoinsulinemic actionDose of test Plasma compound glucose Insulin Test compound (mg/kg)(mg/dl) (ng/ml) Control 0 507 43 Example 2 10 313 26 Example 23 10 38228 Example 32 10 402 30 Example 42 10 308 27

Experimental Example 5 Triglyceride Accumulation Promoting Action in3T3-L1 cells

[0708] A culture medium of 80% confluent 3T3-L1 cells was removed andthe cells were dissociated with 0.25% trypsin-EDTA solution. 5% FBS-DMEM(the same amount as the removed medium) was added and the obtained cellsuspension was centrifuged at 25° C., 100×g for 1 min to give cellsediment and the supernatant was removed. The cells were re-suspended ina suitable amount of 5% FBS-DMEM medium and the cells were counted. 5%FBS-DMEM medium was added to adjust the concentration to 1×10⁵ cells/mland the mixture was dispensed by 1 ml to a 24 well plate. The cells werecultured with aeration of 5% CO₂ at 37° C. for 2 days. Upon confirmationof a post-confluent state, the culture supernatant was changed to amedium containing 0.5 mM-IBMX, and the cells were cultured for 2 days.Then, the medium was changed to a medium containing 10 ng/ml insulin and10⁻⁷ M test compound and the cells were cultured further for 4 days.After removing the culture supernatant, the cells were lysed in a 0.1%SDS solution and the triglyceride amount was measured. The triglycerideaccumulation (%) due to the potentiation of insulin activity by the testcompound was calculated from the following formula. The results areshown in Table 5.

[(triglyceride amount with addition of test compound−triglyceride amountof control)/triglyceride amount of control]×100

[0709] TABLE 5 Triglyceride accumulation promoting action Triglycerideaccumulation Test compound (%) Example 2 260.4 Example 5 233.0 Example 8275.5 Example 16 288.9 Example 21 284.9 Example 23 214.2 Example 32181.2 Example 33 222.5 Example 37 277.3 Example 39 258.0 Example 40231.0 Example 42 193.6 Example 62 327.8

Effect of the Invention

[0710] The heterocyclic compound [I] and a pharmaceutically acceptablesalt of the present invention show a superior hypoglycemic action, ablood hypolipidemic action, an insulin resistance-improving action and aPPAR activating action and are useful as hypoglycemic agents,hypolipidemic agents, insulin resistance improvers, therapeutic agentsof diabetes, therapeutic agents of diabetic complications, glucosetolerance improvers, anti-atherosclerosis agents, anti-obesity agents,antiinflammatory agents, agents for the prophylaxis or treatment ofPPAR-mediated disease and agents for the prophylaxis or treatment ofsyndrome X. Therefore, the heterocyclic compound [I] and apharmaceutically acceptable salt of the present invention are useful forthe prophylaxis or treatment of diabetes, diabetic complications,hyperlipidemia, atherosclerosis, hyperglycemia, diseases caused byinsulin resistant impaired glucose tolerance and diseases caused byinsulin resistance, obesity, inflammation, PPAR-mediated disease andsyndrome X. The heterocyclic compound [I] of the present invention has astructure completely different from the structure of the compoundsheretofore used as an active ingredient of conventional insulinresistance improvers. By the provision of this compound, hypoglycemicagents, hypolipidemic agents, insulin resistance improvers, therapeuticagents of diabetes, therapeutic agents of diabetic complications,glucose tolerance improvers, anti-atherosclerosis agents, anti-obesityagents, antiinflammatory agents, agents for the prophylaxis or treatmentof PPAR-mediated disease and agents for the prophylaxis or treatment ofsyndrome X come to have a wide variety, from which a desired agent canbe freely selected.

[0711] This application is based on patent application Nos. 345543/1999and 295108/2000 filed in Japan, the contents of which are herebyincorporated by reference.

What is claimed is
 1. A heterocyclic compound of the formula [I]

wherein R¹ is hydrogen atom or lower alkyl, R² is hydrogen atom, alkyloptionally having a substituent, cycloalkyl, cycloalkylalkyl, aryloptionally having a substituent, arylalkyl optionally having asubstituent, alkenyl optionally having a substituent, alkynyl optionallyhaving a substituent, heterocyclic alkyl optionally having a substituentor —COR⁴ wherein R⁴ is hydrogen atom, alkyl optionally having asubstituent,, aryl optionally having a substituent, alkenyl optionallyhaving a substituent, arylalkyl optionally having a substituent orheterocyclic residue optionally having a substituent R³ is hydrogenatom, lower alkyl or lower alkoxy, A is a single bond or >N—R⁵ whereinR⁵ is hydrogen atom or lower alkyl, B is lower alkylene, and Y is aryloptionally having a substituent or an aromatic heterocyclic residueoptionally having a substituent or a pharmaceutically acceptable saltthereof:
 2. The heterocyclic compound of claim 1, wherein, in theformula [I], R¹ is hydrogen atom or lower alkyl, R² is hydrogen atom,alkyl optionally having a substituent, cycloalkyl, cycloalkylalkyl, aryloptionally having a substituent, arylalkyl optionally having asubstituent or —COR⁴ wherein R⁴ is hydrogen atom, alkyl optionallyhaving a substituent, aryl optionally having a substituent or arylalkyloptionally having a substituent, R³ is hydrogen atom, lower alkyl orlower alkoxy, A is a single bond or >N—R⁵ wherein R⁵ is hydrogen atom orlower alkyl, B is lower alkylene, and Y is aryl optionally having asubstituent or an aromatic heterocyclic residue optionally having asubstituent, or a pharmaceutically acceptable salt thereof.
 3. Theheterocyclic compound of claim 1, wherein, in the formula [I], R¹ ishydrogen atom or lower alkyl, R² is hydrogen atom, alkyl,cycloalkylalkyl, arylalkyl optionally having a substituent, alkenyl,alkynyl, heterocyclic alkyl or —COR⁴ wherein R⁴ is alkyl, alkenyl oraryl, R³ is hydrogen atom or lower alkoxy, A is a single bond or >N—R⁵wherein R⁵ is lower alkyl, B is lower alkylene, and Y is aryl or anaromatic heterocyclic residue optionally having a substituent, or apharmaceutically acceptable salt thereof.
 4. The heterocyclic compoundof claim 1, wherein, in the formula [I], R¹ is hydrogen atom or loweralkyl, R² is hydrogen atom, alkyl, cycloalkylalkyl, arylalkyl optionallyhaving a substituent or —COR⁴ wherein R⁴ is alkyl or aryl, R³ ishydrogen atom, A is a single bond or >N—R⁵ wherein R⁵ is lower alkyl, Bis lower alkylene, and Y is an aromatic heterocyclic residue optionallyhaving a substituent, or a pharmaceutically acceptable salt thereof. 5.The heterocyclic compound of claim 1, wherein, in the formula [I], Y—A—is

wherein R^(A) is isopropyl or tert-butyl, R^(B) is isopropyl ortert-butyl, R^(C) is isopropyl, tert-butyl, phenyl, thiophen-2-yl,2-methylpropenyl, 3-butenyl, cyclopropyl, 1-butenyl or2,2-dimethylpropyl, or a pharmaceutically acceptable salt thereof. 6.The heterocyclic compound of claim 1, wherein, in the formula [I], Y—A—is

wherein R^(A) is isopropyl or tert-butyl, R^(B) is isopropyl ortert-butyl, R^(C) is isopropyl, tert-butyl, phenyl, thiophen-2-yl,2-methylpropenyl or 3-butenyl, or a pharmaceutically acceptable saltthereof.
 7. The heterocyclic compound of claim 1, wherein, in theformula [I], Y—A— is

or a pharmaceutically acceptable salt thereof.
 8. The heterocycliccompound of claim 1, wherein, in the formula [I], Y—A— is

or a pharmaceutically acceptable salt thereof.
 9. The heterocycliccompound of claim 1, wherein the heterocyclic compound of the formula[I] is any of the following compounds (1) to (67): (1)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (2)2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (3)2-acetyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (4)2-methyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (5)2-hexanoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (6)2-hexyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (7)2-isobutyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (8)2-cyclohexylmethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (9)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(3-phenylpropyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (10)2-benzoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (11)2-benzyl-7-[2-(N-methyl-N-(pyridin-2-yl)amino)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (12)2-benzyl-7-[2-(5-ethyl-pyridin-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (13)2-benzyl-7-[2-(indolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (14) ethyl2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,(15) methyl7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,(16)2-(4-methoxybenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (17) ethyl2-(4-methoxybenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,(18)2-(4-methylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (19) ethyl2-(4-methylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,(20)2-benzyl-7-[2-(6-carboxyindolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (21)2-(4-fluorobenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (22)2-(2,2-dimethylpropionyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (23)2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (24)2-benzyl-7-[2-(5-methyl-2-tert-butyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (25)2-benzyl-7-[2-(5-methyl-2-(thiophen-2-yl)oxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (26)2-benzyl-7-[2-(5-methyl-2-isopropyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (27)2-butyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (28)2-benzyl-7-{2-[5-methyl-2-(2-methylpropenyl)oxazol-4-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (29)2-benzyl-7-{2-[2-(3-butenyl)-5-methyloxazol-4-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (30)2-allyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (31)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(2-propynyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (32)2-(2-butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (33)2-benzyl-7-[(indolin-3-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (34)2-(3-butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (35)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-pentanoyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (36)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(4-pentenoyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (37)2-(3-methyl-2-butenoyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (38)2-(3,3-dimethylbutyryl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (39)2-benzyl-7-methoxy-6-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3RS)-carboxylicacid, (40)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (41)2-benzyl-7-(3-methyl-3-phenylbutoxy)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (42)2-benzyl-7-(3,3-dimethyl-4-phenylbutoxy)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (43)2-benzyl-7-(2-isopropylbenzoxazol-6-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (44)2-benzyl-7-(2-tert-butylbenzoxazol-6-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (45)2-benzyl-7-(2-tert-butylbenzoxazol-5-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (46)7-(2-tert-butylbenzoxazol-6-yl)methoxy-2-(2,2-dimethylpropyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (47)2-benzyl-7-(2-isopropylbenzoxazol-5-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (48)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (49)7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-[(pyridin-2-yl)carbonyl]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (50) methyl2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,(51)2-benzyl-7-[2-(2-cyclopropyl-5-methyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (52)2-(3-methyl-2-butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (53)2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-tert-butyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (54)2-benzyl-7-[2-(1-butenyl)-5-methyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (55)2-benzyl-7-[2-(2,2-dimethylpropyl)-5-methyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (56) ethyl2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate,(57)7-(benzofran-2-ylmethoxy)-2-benzyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (58)2-isobutyryl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (59)7-[2-(benzofran-2-yl)ethoxy]-2-benzyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (60)7-[2-(5-ethylpyridin-2-yl)ethoxy]-2-hexanoyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (61)2-carboxymethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (62)2-[3-(methoxycarbonyl)propionyl]-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (63)2-[3-(ethoxycarbonyl)propyl]-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (64)2-benzyl-6-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3RS)-carboxylicacid, (65)2-(3-acetylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, (66)2-(2-acetylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, and (67)2-benzyl-7-[(5-methyl-2-phenyloxazol-4-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylicacid, or a pharmaceutically acceptable salt thereof.
 10. Theheterocyclic compound of claim 9, wherein the heterocyclic compound ofthe formula [I] is any of the above-mentioned compounds (1) to (47), ora pharmaceutically acceptable salt thereof.
 11. The heterocycliccompound of claim 9, wherein the heterocyclic compound of the formula[I] is any of the above-mentioned compounds (1) to (21), or apharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition comprising the heterocyclic compound of any of claim 1 toclaim 11 or a pharmaceutically acceptable salt thereof.
 13. Apharmaceutical agent comprising the heterocyclic compound of any ofclaim 1 to claim 11 or a pharmaceutically acceptable salt thereof, whichis selected from the group consisting of a hypoglycemic agent, ahypolipidemic agent, an insulin resistance improver, a therapeutic agentof diabetes, a therapeutic agent of diabetic complication, a glucosetolerance improver, an anti-atherosclerosis agent, an anti-obesityagent, an antiinflammatory agent, an agent for the prophylaxis ortreatment of PPAR-mediated disease and an agent for the prophylaxis ortreatment of syndrome X.
 14. A hypoglycemic agent comprising theheterocyclic compound of any of claim 1 to claim 11 or apharmaceutically acceptable salt thereof.
 15. A hypolipidemic agentcomprising the heterocyclic compound of any of claim 1 to claim 11 or apharmaceutically acceptable salt thereof.
 16. An insulin resistanceimprover comprising the heterocyclic compound of any of claim 1 to claim11 or a pharmaceutically acceptable salt thereof.
 17. A therapeuticagent of diabetic complication comprising the heterocyclic compound ofany of claim 1 to claim 11 or a pharmaceutically acceptable saltthereof.
 18. A therapeutic agent of diabetes comprising the heterocycliccompound of any of claim 1 to claim 11 or a pharmaceutically acceptablesalt thereof.